Nonsteroidal antiinflammatory agents

ABSTRACT

are useful in the treatment of inflammation.

This invention relates to the use of nonsteroidal compounds for theproduction of pharmaceutical agents for treatment of inflammations,selected compounds and production processes thereof.

In addition to a large number of steroid compounds, which bind well tothe glucocorticoid receptor and have an antiinflammatory action(glucocorticoids), nonsteroidal compounds are known that namely bind tothe glucocorticoid receptor, for which to date no antiinflammatoryaction has been shown, however [cf. Nature Medicin [Nature Medicine] 4(1998) 92, Mol. Pharmacol. 52 (1997) 571]. In addition, nonsteroidalcompounds were described that are derived from steroidal compounds, havean affinity to the glucocorticoid receptor and probably have anantiinflammatory action that is mediated by the receptor [J. Med. Chem.36, (1993), 3278-3285]. In animal experiments, however, these compoundsdid not show any advantages relative to steroidal glucocorticoids, i.e.,it was not possible to separate the antiinflammatory action from themetabolic effects, e.g., suppression of the suprarenal function.

From WO 98/54159, nonsteroidal compounds are known that have a highgestagenic activity. In the document, there is the observation that theclaimed compounds partially also have action on the glucocorticoidand/or mineral corticoid receptor. In this connection, however, there isneither actual mention of compounds nor disclosure of test results. Thatis to say that from the pool of generically claimed compounds of WO98/54159, compounds that are not specified in more detail are known thathave both high gestagenic activity and action on the glucocorticoidreceptor. In terms of industrial applicability, however, compounds thathave a selectivity with respect to the above-mentioned actions areadvantageous.

In turn, from WO 00/32584, phenol derivatives that have a dissociationof action between antiinflammatory action and undesirable metabolic sideeffects are known as nonsteroidal antiinflammatory agents.

The compounds that are disclosed in the prior art are still in need ofimprovement with respect to their dissociation of action betweenantiinflammatory action and the undesirable side effects.

The object was therefore to make available new nonsteroidalantiinflammatory agents that show a dissociation of action that is atleast as good or better than the compounds of the prior art.

Nonsteroidal compounds have now been found that bind well to theglucocorticoid receptor and, mediated by this bond, produce anantiinflammatory action. In the experiment, these compounds show asignificantly better or at least equally good dissociation of actionbetween antiinflammatory and undesirable actions and are superior to thepreviously described nonsteroidal glucocorticoids or have at least justas good an action.

According to this invention, the following compounds of general formulaI that have an antiinflammatory action are suitable for use for theproduction of pharmaceutical agents:

in which

-   -   R¹ and R² are the same or different and stand for a hydrogen        atom, a C₁-C₅-alkyl group, or, together with the C-atom of the        chain, stand for a ring with a total of 3-7 links,    -   R³ stands for a straight-chain or branched C₁-C₅-alkyl group or        a straight-chain or branched, partially or completely        fluorinated C₁-C₅-alkyl group,    -   A stands for the group    -    (the dashed line means the interface site), in which    -   R⁴ to R⁸ are the same or different from one another and mean a        hydrogen atom, a halogen atom, a cyano group, a nitro group, a        COOR⁹ group        -   whereby R⁹ stands for a hydrogen atom, a straight-chain or            branched C₁-C₅-alkyl group or a benzyl group,        -   a CONR¹⁰ group,        -   whereby R¹⁰ stands for a hydrogen atom or a straight-chain            or branched C₁-C₅-alkyl group,        -   an NHR¹¹ group,        -   whereby R¹¹ stands for a hydrogen atom, a straight-chain or            branched C₁-C₅-alkyl group, a straight-chain or branched,            partially or completely fluorinated C₁-C₅-alkyl group, a            C₁-C₅-acyl group, an —SO₂—(C₁-C₅)alkyl group or an            —SO₂-phenyl group that is optionally substituted by halogen            or a C₁-C₅-alkyl group,        -   a straight-chain or branched C₁-C₅-alkyl group, a            straight-chain or branched C₂-C₅-alkenyl group, a            straight-chain or branched C₂-C₅-alkinyl group, a            straight-chain or branched C₁-C₅-alkyl group that is            partially or completely substituted by fluorine atoms, a            C₁-C₅-acyl group, an aryl radical or a heteroaryl radical,    -   R⁴ and R⁵ together with the two carbon atoms of ring A mean a        saturated or unsaturated carbocyclic ring with a total of 5-7        links,    -   Ar stands for a ring system, selected from the group of general        partial formula 1 or 2,        in which    -   radicals X^(3a), X^(3b), X⁴, X⁶, X⁷ (in partial formula 1) and        Y⁴, Y⁵, Y⁷, and Y⁸ (in partial formula 2) are the same or        different and mean a hydrogen atom, a straight-chain or branched        C₁-C₅-alkyl group, or a straight-chain or branched, partially or        completely fluorinated C₁-C₅-alkyl group,    -   radicals X⁴, X⁶, X⁷ (in partial formula 1) or Y⁵, Y⁷, Y⁸ (in        partial formula 2) in addition are the same or different and        mean a hydrogen atom, a halogen atom, a hydroxy group, a        C₁-C₅-alkoxy group or a C₁-C₅-alkanoyloxy group,        as well as their racemates or separately present stereoisomers,        and optionally their physiologically compatible salts.

The compounds of general formula I according to the invention can bepresent as different stereoisomers because of the presence of asymmetrycenters. Both the racemates and the separately present stereoisomers arepart of the subject matter of this invention.

A special subject of this invention are the isomers that turn the planeof polarized light in the way that they are referred to as(+)-compounds.

The substituents that are defined as groups or radicals in the compoundsof general formula I can have the meanings below in each case.

The C₁-C₅-alkyl groups R¹, R², R³, R⁴, R⁵, R¹², X^(n), and Y^(o) can bestraight-chain or branched and can stand for a methyl-, ethyl-,n-propyl-, iso-propyl-, n-butyl, iso-butyl, tert-butyl or n-pentyl,2,2-dimethylpropyl-, 2-methylbutyl- or 3-methylbutyl group. A methylgroup or ethyl group is preferred.

If R¹ and R² together with the C-atom of the chain form a 3- to7-membered ring, the latter optionally can be substituted by 1-2 oxygenatoms and can be, for example, a cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl ring.

For a partially or completely fluorinated C₁-C₅-alkyl group, thepartially or completely fluorinated alkyl groups that appear above areconsidered. Of the latter, the trifluoromethyl group or pentafluoroethylgroup, as well as as partially fluorinated alkyl groups, for example,the 5,5,5,4,4-pentafluoropentyl group or 5,5,5,4,4,3,3-heptafluoropentylgroup, are preferred. The trifluoromethyl group and the pentafluoroethylgroup are preferred.

The substituents of phenyl ring A, independently of one another, canhave the meanings that are defined in the claims, such as a hydrogenatom, a halogen atom, a cyano group, a nitro group, an NHR¹¹ group,whereby R¹¹ stands for a hydrogen atom, a straight-chain or branchedC₁-C₅-alkyl group, a straight-chain or branched, partially or completelyfluorinated C₁-C₅-alkyl group, a C₁-C₅-acyl group, an —SO₂—(C₁-C₅)alkylgroup or an —SO₂-phenyl group that is optionally substituted by halogenor a C₁-C₅-alkyl group, a straight-chain or branched C₁-C₅-alkyl group,a straight-chain or branched C₂-C₅-alkenyl group, a straight-chain orbranched C₂-C₅-alkinyl group, a straight-chain or branched C₁-C₅-alkylgroup that is partially or completely substituted by fluorine atoms, aC₁-C₅-acyl group, an aryl radical or a heteroaryl radical.

Preferred are phenyl rings A, which carry 1-3 non-hydrogen substituents.

In addition, R⁴ and R⁵ together with the two carbon atoms of ring A canmean a saturated or unsaturated carbocyclic ring with a total of 5 to 7links, such as, for example, indane, naphthalene, tetrahydronaphthalene,benzocycloheptane.

A subject of the invention is the use of the compounds of generalformula I in which R⁴ to R⁸ are the same or different from one anotherand mean a hydrogen atom, a halogen atom, a cyano group, a nitro group,a COOR⁹ group, whereby R⁹ stands for a hydrogen atom, a straight-chainor branched C₁-C₅-alkyl group or a benzyl group, a CONR¹⁰ group, wherebyR¹⁰ stands for a hydrogen atom or a straight-chain or branchedC₁-C₅-alkyl group, an NHR¹¹ group, whereby R¹¹ stands for a hydrogenatom, a straight-chain or branched C₁-C₅-alkyl group, a straight-chainor branched, partially or completely fluorinated C₁-C₅-alkyl group, aC₁-C₅-acyl group, an —SO₂—(C₁-C₅)alkyl group or an —SO₂-phenyl groupthat is optionally substituted by halogen or a C₁-C₅-alkyl group, astraight-chain or branched C₁-C₅-alkyl group, a straight-chain orbranched C₁-C₅-alkenyl group, a straight-chain or branched C₁-C₅-alkinylgroup, a straight-chain or branched C₁-C₅-alkyl group that is partiallyor completely substituted by fluorine atoms, a C₁-C₅-acyl group, an arylradical or a heteroaryl radical.

The designation halogen atom or halogen means a fluorine, chlorine,bromine or iodine atom. Preferred is a fluorine, chlorine or bromineatom.

For a C₂-C₅-alkenyl group, for example, a vinyl, 2-substituted vinylgroup, 1-propenyl, 2-propenyl, 2- or 3-substituted 2-propenyl group,1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl,2-methyl-2-propenyl, 1-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl,and 3-methyl-1-butenyl group are considered. Preferred are the alkenylgroups, which carry the double bond in 1- or 2-position. As substituentsfor the vinyl group or the propenyl group, primarily the methyl group orthe ethyl group is suitable.

A C₂-C₅-alkinyl group is defined as, for example, an ethinyl,1-propinyl, 2-propinyl, I-butinyl, 2-butinyl, 3-methyl-1-butinyl,4-methyl-1-butinyl or 1-pentinyl group. Preferred are the alkinyl groupsthat carry a triple bond in 1-position or 2-position.

With the C₁-C₅-acyl group, for example, a formyl, acetyl, propionyl,n-butyroyl, 2-methylpropionyl, n-valeroyl, 2-methylbutyroyl,3-methylbutyroyl or a pivaloyl group is meant.

With a sulfonyl(C₁-C₅)-alkyl group R¹¹, for example, a methylsulfonylgroup or an ethylsulfonyl group is meant.

For the sulfonylphenyl group R¹¹ that is optionally substituted byhalogen or a C₁-C₅-alkyl group, 2-chloro(phenylsulfonyl),3-chloro(phenylsulfonyl), 4-chloro(phenylsulfonyl),2-methyl(phenylsulfonyl), 3-methyl(phenylsulfonyl), and4-methyl(phenylsulfonyl) can be mentioned. The sulfonyl group is bondedwith its free valency to the nitrogen atom of the NHR¹¹ group.

Aryl means a phenyl group or a substituted phenyl group.

As substituents of the aryl group, halogen atoms, the cyano, nitro,C₁-C₅-alkoxy, amino, hydroxy, carboxy and C₁-C₅-alkanoyl groups,branched and unbranched C₁-C₅-alkyl groups, branched and unbranchedC₁-C₅-alkyl groups, which can be partially or completely fluorinated,are suitable.

Heteroaryl comprises aromatic heterocyclic 5- and 6-rings, which cancontain in the ring 1-3 additional heteroatoms from the group of oxygen,nitrogen or sulfur. Preferred are heterocyclic five-membered rings. Inparticular, furyl, thienyl, pyridyl, thiazolyl, oxazolyl, oxadiazolyl,and imidazolyl can be mentioned.

The heteroaryl groups optionally can be substituted by branched andunbranched C₁-C₅-alkyl groups, branched and unbranched C₁-C₅-alkylgroups that can be fluorinated and/or halogen atoms.

The hydroxy groups that are possible for radicals X^(n), Y^(o) canoptionally be defined below as ethers or esters:

As a C₁-C₅-alkyl group for etherification of hydroxy groups, theabove-mentioned alkyl groups are suitable, especially a methyl group orethyl group.

As a C₁-C₅-alkanoyl group for esterification of hydroxy groups, aformyl, acetyl, propionyl, butyryl, iso-butyryl, valeryl or iso-valerylor pivaloyl group is considered, preferably an acetyl group.

As a C₁-C₅-acyl group for esterification of hydroxy groups, for example,the above-mentioned alkanoyl groups, preferably in turn an acetyl group,or a benzoyl, toluoyl, phenylacetyl, acryloyl, cinnamoyl orcyclohexylcarbonyl group, can be mentioned.

As a C₁-C₅-alkanoyloxy group for X⁴, X⁶, Y⁴, Y⁵, Y⁷ or Y⁸, a formyloxy,acetoxy, propionyloxy, butyryloxy, iso-butyryloxy, valeryloxy oriso-valeryloxy group is considered, preferably an acetoxy group.

Preferred are compounds in which Ar stands for partial formula 2, and Y⁴means a methyl group.

Especially preferred are compounds in which Ar stands for partialformula 2, Y⁴ means a methyl group, and the other substituents Y⁵, Y⁷and Y⁸ mean hydrogen.

Nonsteroidal compounds as such with a mixed profile that consists ofgestagenic and androgenic activity in different manifestations arealready the subject of WO 98/54159. The compounds of general formula Iaccording to claim 1 that are to be used according to this patentapplication for the production of pharmaceutical agents withantiinflammatory action fall within the scope of the general formulathat is contained in WO 98/54159, but are not preferred as a group ordirectly disclosed as compounds there. They are thus novel and also meetthe patenting requirement of inventive activity because of theantiinflammatory action that was found and that is dissociated fromundesirable metabolic effects or other effects.

Undesirable actions/effects in the context of this invention aremetabolic actions or else bonds to other steroid receptors.

The compounds of general formula I cited by name below fall namelywithin the scope of the general formula that is cited in WO 98/54159 butare not previously described by name there. They are thus novel and alsomeet the patenting requirement of inventive activity because of theantiinflammatory action that was found and that is dissociated fromundesirable side effects.

These compounds as such therefore also belong to the subject matter ofthis invention and are listed below.

Their naming is to be illustrated in the following example:

-   6-[4-(2-Chloro-3-R⁵-4-R⁶-5-R⁷-6-R⁵-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

The following compounds are the subject of this invention:

-   0.5-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide-   6-[4-(2-chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   5-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide-   6-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   5-[4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide-   6-[4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-bromo-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[4-(indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(5-fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1′-one-   (−)    6-[4-(5-fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[4-(5-fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[4-(3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[4-(3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-cyano-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-ethenyl-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-ethyl-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(5-fluoro-2-phenylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-{5-fluoro-2-(furan-2′-yl)phenyl}-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-Valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-chloro-3-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2-chloro-3-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2-chloro-3-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-chloro-4-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2-chloro-4-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2-chloro-4-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-chloro-6-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2-chloro-6-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2-chloro-6-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2,3-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2,3-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2,3-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl    valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2,4-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2,4-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2,4-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2,5-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2,5-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2,5-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[4-(4-bromo-2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(4-bromo-2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(4-bromo-2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-chloro-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2-chloro-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2-chloro-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2,3)-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2,4-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2,4-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2,4-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2,3,5-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2,3,5-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2,3,5-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2,3,4-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2,3,4-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2,3,4-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(3-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(3-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(3-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(4-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(4-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(4-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[4-(5-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(5-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(5-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[4-(5-chloro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(5-chloro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(5-chloro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[3-{1-(2-chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[3-{1-(2-chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-chlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2-chlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2-chlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-chlorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2-chlorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2-chlorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-chloro-4-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-chloro-4-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-chloro-5-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-chloro-5-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclobutyl-}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2,4-dichlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2,4-dichlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2,4-dichlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2,4-dichlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2,4-dichlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2,4-dichlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-trifluoromethyl-phenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[3-{1-(2-trifluoromethyl-phenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin    1-one-   (+)    6-[3-{1-(2-trifluoromethyl-phenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-fluorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2-fluorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2-fluorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-fluorophenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2-fluorophenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2-fluorophenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2,3-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2,3-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2,3-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2,3-difluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[3-{1-(2,3-difluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[3-{1-(2,3-difluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2,5-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2,5-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2,5-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2,3,5-trifluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2,3,5-trifluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[3-{1-(2-bromophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[3-{1-(2-bromophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[3-{1-(2-bromophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[2-hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[2-hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[2-hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide-   (−)    5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide-   (+)    5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide-   6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide-   (−)    5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide-   (+)    5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide-   5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide-   (−)    5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide-   (+)    5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide-   6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)-6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)-6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one-   6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one-   (−)    6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one-   (+)    6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one-   6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one-   (−)    6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one-   (+)    6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one

A special aspect of this invention are the above-indicated2,3-benzoxazin-1-ones.

Another aspect of this invention are the above-indicated compounds,whose 2,3-benzoxazin-1-one in 3-position carries a methyl group.

If the compounds of general formula I are present as salts, this can be,for example, in the form of hydrochloride, sulfate, nitrate, phosphate,pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate orsuccinate.

If the compounds according to the invention are present as racemicmixtures, they can be separated into the pure, optically active formsaccording to the methods of racemate separation that are familiar to oneskilled in the art. For example, the racemic mixtures can be separatedinto the pure isomers by chromatography on an even optically activecarrier material (CHIRALPAK AD®). It is also possible to esterify thefree hydroxy group in a racemic compound of general formula I with anoptically active acid and to separate the diastereoisomer esters thatare obtained by fractionated crystallization or by chromatography and tosaponify the separated esters in each case to form the optically pureisomers. As an optically active acid, for example, mandelic acid,camphorsulfonic acid or tartaric acid can be used.

Process for the Production of the Compounds According to the Invention

The compounds according to the invention can be obtained by the chainC(R¹)(R²)—CH₂—C(OH)(R³)—B—NH—Ar being built up starting from acommercially available phenyl compound or a phenyl compound that isavailable according to known methods, whereby radical R³ is introducedin the last step or the ring system of formulas (1) or (2) (=Ar) isintroduced with the formation of the amide bond B—NH—Ar.

Compounds that were produced according to one of the processes below andin which A is a substituted aromatic ring optionally can be substitutedselectively at this aromatic radical according to known processes.Examples of this process are the catalytic hydrogenation of multiplebonds, the nitration and the halogenation. Halogen and nitrosubstitutions offer, moreover, possible further modifications. Thus, forexample, aryl bromides can be reacted with boron, tin or zinc reagentsunder palladium catalysis in the way that is known to one skilled in theart. Nitro compounds can be reduced to aniline derivatives, for examplehydrogenolytically, or with metals, such as, e.g., iron or zinc. Theaniline derivatives can be further reacted after diazotization in aknown way, for example in terms of Sandmeyer reactions.

(A)

An α-ketocarboxylic acid of general formula II

in which A, R¹ and R² have the meanings that are indicated in formula I,is either optionally esterified with a compound of general formula(R¹²)₃SiR³  (III)in which R³ has the meaning that is indicated in general formula I, andR¹² means a C₁-C₅-alkyl group,in the presence of a catalyst, or is reacted with an alkyl metalcompound, for example a Grignard reagent or a lithium alkyl, to form acompound of formula IV

As catalysts, fluoride salts or basic compounds, such as alkalicarbonates, are suitable (J. Am. Chem. Soc. 111, 393 (1989)).

The ester is optionally cleaved again and then reacted with a compoundof general formula VAr—NH—R¹³,  (V)whereby R¹³ means a hydrogen atom or a C₁-C₅ acyl group, and Ar has themeaning that is indicated in general formula I,whereby then radical R¹³ is cleaved off to obtain a compound of formulaI oris reacted directly with a compound of general formulaAr—NH—R¹³ (V)whereby R¹³ means a hydrogen atom or a C₁-C₅-acyl group, and Ar has themeaning that is indicated in general formula I,optionally after activation of the acid function by, e.g., conversioninto the acid chloride, whereby then radical R¹³ is cleaved off in anysequence and is reacted with a compound of general formula III(R¹²)₃—SiR³  (I)in which R³ and R¹² have the above-indicated meanings, to obtain acompound of formula 1.(B)

A compound of general formula VI

in which A, B, R¹, R², and R³ have the meaning that is indicated informula I and LG means any leaving group, is reacted with a compound ofgeneral formula VAr—NH—R¹³  (V)whereby R¹³ means a hydrogen atom or a C₁-C₅ acyl group, and Ar has themeaning that is indicated in general formula I, whereby then radical R¹³is cleaved off to obtain a compound of formula I.

In this case, the compound of general formula VI can optionally also beformed only as intermediate product, which can be isolated, if desired,or else can be produced only in situ, e.g., this can be an acid chloridethat is formed intermediately from a corresponding carboxylic acid. Asleaving groups, in this respect, for example, a fluorine, chlorine orbromine atom, or, if no intermediate acid chloride is formed, themesylate radical or tosylate radical, can be mentioned.

The binding of substances to the glucocorticoid receptor (GR) isexamined with the aid of a recombinantly produced receptor. Cytosolpreparations of Sf9 cells, which had been infected with recombinantbaculoviruses, which code for the GR, are used for the binding studies.In comparison to the reference substance [³H]-dexamethasone, thesubstances show a high to very high affinity to the GR.

In addition, these compounds in the mineral corticoid receptor(MR)-binding test with use of cytosol preparations that consist of Sf9cells, which had been infected with baculoviruses that code for the MR,and with use of [³H]-aldosterone as a reference substance, showaffinities to the MR.

As an essential molecular mechanism for the antiinflammatory action ofglucocorticoids, the GR-mediated inhibition of the transcription ofcytokines, adhesion molecules, enzymes and other pro-inflammatoryfactors can be seen. This inhibition is produced by an interaction ofthe GR with other transcription factors, e.g., AP-1 and NF-kappa-B (fora survey, see Cato, A. C. B. and Wade, E., BioEssays 18, 371-378, 1996).

The compounds of general formula I according to the invention inhibitthe secretion of the cytokine IL-8 that is triggered bylipopolysaccharide (LPS) in human monocyte cell line THP-1. Theconcentration of the cytokines was determined in the supernatant withuse of commercially available ELISA kits.

The antiinflammatory actions of the compounds of general formula I weretested in the animal experiment by testing in the croton oil-inducedinflammation in rats and mice (J. Exp. Med. (1995), 182, 99-108). Inthis connection, croton oil in ethanolic solution was administeredtopically to the animals' ears. The test substances were alsoadministered topically or systemically simultaneously with or two hoursbefore the croton oil. After 16-24 hours, the ear weight was measured asa yardstick of the inflammatory edema, the peroxidase activity wasmeasured as a yardstick of the invasions of granuloctyes, and theelastase activity was measured as a yardstick of the invasions ofneutrophilic granuloctyes. In this test, the compounds of generalformula I inhibit the three above-mentioned inflammation parameters bothafter topical administration and after systemic administration.

One of the most frequent undesirable effects of a glucocorticoid therapyis the so-called “steroid diabetes” [cf. Hatz, H. J., Glucocorticoide:Immunologische Grundlagen, Pharmakologie und Therapierichtlinien[Glucocorticoids: Immunological Bases, Pharmacology and TherapyGuidelines], Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart,1998]. The reason for this is the stimulation of the gluconeogenesis inthe liver by induction of the enzymes that are responsible for thiseffect and by free amino acids, which develop from the degradation ofproteins (catabolic action of glucocorticoids). A key enzyme of thecatabolic metabolism in the liver is the tyrosinamino transferase (TAT).The activity of this enzyme can be determined photometrically from liverhomogenates and represents a good yardstick of the undesirable metabolicactions of the glucocorticoids. To measure the TAT induction, theanimals are sacrificed 8 hours after the test substances areadministered, the livers are removed, and the TAT activity in thehomogenate is measured. In this test, at doses at which they have anantiinflammatory action, the compounds of general formula I inducelittle or no tyrosinamino transferase.

In summary, the new compounds of general formula I compared to thepreviously used steroidal glucocorticoids have the following advantages:

-   -   nonsteroidal structure (i.e., the substances are also effective        in patients who, because of an allergic reaction to the steroid        basic structures of conventional glucocorticoids, can no longer        access the latter for therapy (cf. Lutz, M. E., el-Azhary R. A.,        Mayo Clin. Proc. 72, 1141-1144, 1997).    -   good antiinflammatory action with little metabolic action

Because of their antiinflammatory and additional antiallergic,immunosuppressive and antiproliferative actions, the compounds ofgeneral formula I according to the invention can be used as medicationsfor treatment or prophylaxis of the following pathologic conditions inmammals and humans: In this case, the term “DISEASE” stands for thefollowing indications:

-   (i) Lung diseases, which coincide with inflammatory, allergic and/or    proliferative processes:    -   Chronically obstructive lung diseases of any origin, mainly        bronchial asthma    -   bronchitis of different origins    -   all forms of restrictive lung diseases, mainly allergic        alveolitis,    -   all forms of pulmonary edema, mainly toxic pulmonary edema    -   sarcoidoses and granulomatoses, especially Boeck's disease-   (ii) Rheumatic diseases/auto-immune diseases/degenerative joint    diseases, which coincide with inflammatory, allergic and/or    proliferative processes:    -   All forms of rheumatic diseases, especially rheumatoid        arthritis, acute rheumatic fever, polymyalgia rheumatica,    -   reactive arthritis    -   inflammatory soft-tissue diseases of other origins    -   arthritic symptoms in degenerative joint diseases (arthroses)    -   traumatic arthritides    -   collagen diseases of other origins, e.g., systemic lupus        erythematodes, scleroderma, polymyositis, dermatomyositis,        Sjögren's syndrome, Still syndrome, Felty's syndrome-   (iii) Allergies, which coincide with inflammatory and/or    proliferative processes:    -   All forms of allergic reactions, e.g., Quincke's edema, hay        fever, insect bites, allergic reactions to pharmaceutical        agents, blood derivatives, contrast media, etc., anaphylactic        shock, urticaria, contact dermatitis-   (iv) Vasculitis    -   Panarteritis nodosa, temporal arteritis, erythema nodosum-   (v) Dermatological diseases, which coincide with inflammatory,    allergic and/or proliferative processes:    -   Atopic dermatitis (mainly in children)    -   psoriasis    -   pityriasis rubra pilaris    -   erythematous diseases, triggered by different noxae, e.g.,        radiation, chemicals, burns, etc.    -   bullous dermatoses    -   diseases of the lichenoid group    -   itching (e.g., of allergic origins)    -   seborrheal eczema    -   rosacea    -   pemphigus vulgaris    -   erythema exudativum multiforme    -   balanitis    -   vulvitis    -   hair loss, such as alopecia areata    -   cutaneous T-cell lymphoma-   (vi) Nephropathies, which coincide with inflammatory, allergic    and/or proliferative processes:    -   Nephrotic syndrome    -   all nephritides-   (vii) Liver diseases, which coincide with inflammatory, allergic    and/or proliferative processes:    -   Acute liver cell decomposition    -   acute hepatitis of different origins, e.g., virally-, toxically-        or pharmaceutical agent-induced    -   chronically aggressive and/or chronically intermittent hepatitis-   (viii) Gastrointestinal diseases, which coincide with inflammatory,    allergic and/or proliferative processes:    -   Regional enteritis (Crohn's disease)    -   ulcerative colitis    -   gastritis    -   reflux esophagitis    -   gastroenteritides of other origins, e.g., native sprue-   (ix) Proctological diseases, which coincide with inflammatory,    allergic and/or proliferative processes:    -   Anal eczema    -   fissures    -   hemorrhoids    -   idiopathic proctitis-   (x) Eye diseases, which coincide with inflammatory, allergic and/or    proliferative processes:    -   Allergic keratitis, uveitis, iritis    -   conjunctivitis    -   blepharitis    -   optic neuritis    -   chorioiditis    -   sympathetic ophthalmia-   (xi) Diseases of the ear-nose-throat area, which coincide with    inflammatory, allergic and/or proliferative processes:    -   Allergic rhinitis, hay fever    -   otitis externa, e.g., caused by contact dermatitis, infection,        etc.    -   otitis media-   (xii) Neurological diseases, which coincide with inflammatory,    allergic and/or proliferative processes:    -   Cerebral edema, mainly tumor-induced cerebral edema    -   multiple sclerosis    -   acute encephalomyelitis    -   meningitis    -   different forms of convulsions, e.g., infantile nodding spasms-   (xiii) Blood diseases, which coincide with inflammatory, allergic    and/or proliferative processes:    -   Acquired hemolytic anemia    -   idiopathic thrombocytopenia-   (xiv) Tumor diseases, which coincide with inflammatory, allergic    and/or proliferative processes:    -   Acute lymphatic leukemia    -   malignant lymphoma    -   lymphogranulomatoses    -   lymphosarcoma    -   extensive metastases, mainly in breast, bronchial and prostate        cancers-   (xv) Endocrine diseases, which coincide with inflammatory, allergic    and/or proliferative processes:    -   Endocrine orbitopathy    -   thyrotoxic crisis    -   de Quervain's thyroiditis    -   Hashimoto's thyroiditis    -   hyperthyroidism-   (xvi) Organ and tissue transplants, graft-versus-host disease-   (xvii) Severe shock conditions, e.g., anaphylactic shock, systemic    inflammatory response syndrome (SIRS)-   (xviii) Substitution therapy, with:    -   Innate primary suprarenal insufficiency, e.g., congenital        adrenogenital syndrome    -   acquired primary suprarenal insufficiency, e.g., Addison's        disease, autoimmune adrenalitis, meta-infective, tumors,        metastases, etc.    -   innate secondary suprarenal insufficiency, e.g., congenital        hypopituitarism    -   acquired secondary suprarenal insufficiency, e.g.,        meta-infective, tumors, etc.-   (xix) Vomiting, which coincides with inflammatory, allergic and/or    proliferative processes:    -   e.g., in combination with a 5-HT₃-antagonist in        cytostatic-agent-induced vomiting-   (xx) Pain with inflammatory origins, e.g., lumbago.

The compounds of general formula I according to the invention can alsobe used for therapy and prophylaxis of additional pathologic conditionsthat are not mentioned above, for which synthetic glucocorticoids arenow used (see in this connection Hatz, H. J., Glucocorticoide:Immunologische Grundlagen, Pharmakologie und Therapierichtlinien,Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998).

All previously mentioned indications (i) to (xx) are described in detailin Hatz, H. J., Glucocorticoide: Immunologische Grundlagen,Pharmakologie und Therapierichtlinien, WissenschaftlicheVerlagesgesellschaft mbH, Stuttgart, 1998.

For the therapeutic actions in the above-mentioned pathologicconditions, the suitable dose is different and it depends on, forexample, the active strength of the compound of general formula I, thehost, the type of administration and the type and severity of theconditions that are to be treated, as well as the use as prophylacticagent or therapeutic agent.

In addition, the invention provides

-   -   (i) The use of a compound of the invention according to formula        I or its mixture for the production of a medication for treating        a DISEASE;    -   (ii) a process for treating a DISEASE, and said process        comprises an administration of an amount of compound according        to the invention, whereby the amount suppresses the disease and        whereby the amount of compound is given to a patient who        requires such a medication:    -   (iii) a pharmaceutical composition for treating a DISEASE, and        said treatment comprises one of the compounds according to the        invention or its mixture and at least one pharmaceutical        adjuvant and/or vehicle.

In general, satisfactory results are to be expected in animals when thedaily doses comprise a range of 1 μg to 100,000 μg of the compoundaccording to the invention per kg of body weight. In larger mammals, forexample humans, a recommended daily dose lies in the range of 1 μg to100,000 μg per kg of body weight. Preferred is a dose of 10 to 30,000 μgper kg of body weight, more preferably a dose of 10 to 10,000 μg per kgof body weight. For example, this dose is suitably administered severaltimes daily. For treating acute shock (e.g., anaphylactic shock),individual doses can be given that lie considerably above theabove-mentioned doses.

The formulation of the pharmaceutical preparations based on the newcompounds is carried out in a way that is known in the art, by theactive ingredient being processed with the vehicles, fillers, substancesthat influence decomposition, binding agents, humectants, lubricants,absorbents, diluents, flavoring correctives, staining agents, etc., thatare commonly used in galenicals and converted into the desired form ofadministration. In this case, reference is to be made to Remington'sPharmaceutical Science, 15th Ed. Mack Publishing Company, EastPennsylvania (1980).

For oral administration, especially tablets, coated tablets, capsules,pills, powders, granulates, lozenges, suspensions, emulsions orsolutions are suitable.

For parenteral administration, injection and infusion preparations arepossible.

For intra-articular injection, correspondingly prepared crystalsuspensions can be used.

For intramuscular injection, aqueous and oily injection solutions orsuspensions and corresponding depot preparations can be used.

For rectal administration, the new compounds can be used in the form ofsuppositories, capsules, solutions (e.g., in the form of enemas) andointments, both for systemic and for local therapy.

For pulmonary administration of the new compounds, the latter can beused in the form of aerosols and inhalants.

For local application to eyes, outer ear channels, middle ears, nasalcavities, and paranasal sinuses, the new compounds can be used as drops,ointments and tinctures in corresponding pharmaceutical preparations.

For topical application, formulations in gels, ointments, fattyointments, creams, pastes, powders, milk and tinctures are possible. Thedosage of the compounds of general formula I should be 0.01%-20% inthese preparations to achieve an adequate pharmacological action.

The invention also comprises the compounds of general formula Iaccording to the invention as therapeutic active ingredients. Inaddition, the compounds of general formula I according to the inventionare part of the invention as therapeutic active ingredients togetherwith pharmaceutically compatible and acceptable adjuvants and vehicles.The invention also comprises a pharmaceutical composition that containsone of the pharmaceutically active compounds according to the inventionor mixture thereof and a pharmaceutically compatible salt orpharmaceutically compatible adjuvants and vehicles.

The examples below are used for a more detailed explanation of theinvention without intending that it be limited to these examples. Thesyntheses of important precursors, which are not disclosed within thescope of the experimental part, are already prior art and can be deducedin the example from WO 98/54159.

Experimental Part

EXAMPLE 16-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneEXAMPLE 25-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide

Precursors:

2-(5-Fluoro-2-methylphenyl)-2-methylpropionitrile

5.25 g of (5-fluoro-2-methylphenyl)acetonitrile and 5.25 ml of methyliodide are dissolved in 70 ml of dimethylformamide and mixed with 2.7 gof sodium hydride (80%) for 2.5 hours while being cooled with ice. After3 hours at 0° C. and 16 hours at room temperature, it is mixed with icewater and ethyl acetate, acidified with 1 M hydrochloric acid, and theethyl acetate phase is washed with water, dried (Na₂SO₄) andconcentrated by evaporation. 6.1 g of2-(5-fluoro-2-methylphenyl)-2-methylpropionitrile is obtained as an oil.

2-(5-Fluoro-2-methylphenyl)-2-methylpropionaldehyde

6.1 g of 2-(5-fluoro-2-methylphenyl)-2-methylpropionitrile, dissolved in60 ml of toluene, is mixed at −70° C. for 45 minutes with 44 ml of 1.2 Mdiisobutylaluminum hydride solution in toluene. After 4 hours at −78°C., 120 ml of ethyl acetate is added in drops. It is heated to roomtemperature and washed three times with 2N sulfuric acid and once withwater. The ethyl acetate phase is dried (Na₂SO₄) and concentrated byevaporation. After distillation, 5.3 g of2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde of boiling point120° C./0.031 hPa is obtained.

4-(5-Fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid

A solution of 8.04 ml of 2-diethylphosphono-2-ethoxyacetic acid-ethylester in 40 ml of tetrahydrofuran is mixed with 16.5 ml of a 2 Msolution of lithium diisopropylamide in tetrahydrofuran-heptane-toluenewithin 20 minutes while being cooled with ice, and it is stirred for 30minutes at 0° C. Within 30 minutes, a solution of 5.2 g of2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde in 30 ml oftetrahydrofuran is added in drops to it at 0° C. After 20 hours at roomtemperature, 2N sulfuric acid is added, it is extracted with ethylacetate, dried (Na₂SO₄) and concentrated by evaporation. The crudeproduct is saponified with 100 ml of 2 M sodium hydroxide solution. 5 gof acid is obtained, which is refluxed for several hours with 450 ml of2N sulfuric acid while being stirred vigorously. After extraction withethyl acetate and washing with water, 4 g of4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid is obtained as ayellowish oil.

5-[4-(5-Fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]phthalide

950 mg of 4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid in 15ml of dimethylacetamide is mixed at −10° C. with 0.322 ml of thionylchloride, stirred for 30 minutes at −10° C. and for 1 hour at 0° C. andpurified with 750 mg of 5-aminophthalide. After 16 hours at roomtemperature, it is mixed with 2 M hydrochloric acid and ethyl acetate,the organic phase is washed neutral with water, dried (Na₂SO₄) andconcentrated by evaporation. After chromatography on silica gel withhexane-ethyl acetate (3:2) and recrystallization from diisopropyl ether,486 mg of5-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]phthalide offlash point 153° C. is obtained.

6-[4-(5-Fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

was obtained analogously to5-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]phthalidewith use of 4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid and6-amino-2,3-benzoxazin-1-one, flash point 186° C.

6-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

514 mg of6-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-onein 10 ml of dimethylformamide is purified at 0° C. with 192 mg of cesiumcarbonate and 0.44 ml of trifluoromethyl(trimethyl)silane. After 1 hourat 0° C. and 16 hours at room temperature, it is again cooled to 0° C.and mixed with 1.3 ml of a 1 M tetrabutylammonium fluoride solution intetrahydrofuran. After 30 minutes at 0° C., 2N sulfuric acid and ethylacetate are added, the ethyl acetate phase is washed with water, dried(Na₂SO₄) and concentrated by evaporation. After chromatography on silicagel with hexane-ethyl acetate (3:2), 220 mg of6-[4-(5-fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one,flash point 175-176° C., is obtained.

5-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide

is obtained analogously to Example 1 from5-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]phthalide,flash point 165-168° C.Separation of the Enantiomers of Example 1:

The enantiomer mixture of Example 1 is separated by chromatography onchiral support medium (CHIRALPAK AD®, DAICEL Company) withhexane/ethanol (9:1, vv). Thus obtained from 140 mg of racemate are:

-   (−)    6-[4-(5-Fluoro-2-tolyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one    as a first fraction: 57 mg, [flash point 203-204° C., α_(D)=−92.7°    (c=0.5 in tetrahydrofuran)] and-   (+)    6-[4-(5-Fluoro-2-tolyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one    as a second fraction: 56 mg, [flash point 202-203° C.].

EXAMPLE 36-[4-(2-Chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one

Precursors:

2-(2-Chloro-5-fluorophenyl)-2-methylpropionitrile

Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methyl-propionitrile,2-(2-chloro-5-fluorophenyl)-2-methylpropionitrile is synthesized,boiling point 100° C./0.04 hPa.

2-(2-Chloro-5-fluorophenyl)-2-methylpropionaldehyde

Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,2-(2-chloro-5-fluorophenyl)-2-methylpropionaldehyde, boiling point 120°C./0.04 hPa, is obtained.

4-(2-Chloro-5-fluorophenyl)-4-methyl-2-oxovaleric acid

Analogously to the process that is described for4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid,4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxovaleric acid is obtained as anoil.

6-[4-(2-Chloro-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

is obtained from 4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxovaleric acidand 6-amino-2,3-benzoxazin-1-one analogously to5-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]phthalide,flash point 198-199° C.

6-[4-(2-Chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

was obtained analogously to Example 1 from6-[4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-2,3-benzoxazin-1-one,flash point 201-203° C.Separation of the Enantiomers of Example 3:

The enantiomer mixture of Example 3 is separated by chromatography onchiral support medium (CHIRALPAK AD®, DAICEL Company) withhexane/ethanol (19:1, w). Thus obtained from 190 mg of racemate are:

-   (−)    6-[4-(2-Chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one    as a first fraction: 61 mg, [flash point 247-249° C., α_(D)=−74.2°    (c=0.5 in tetrahydrofuran)], and-   (+)-6-[4-(2-Chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one    as a second fraction: 74 mg, [flash point 247-249° C.]

Analogously to Example 3, the compounds of Tables 1-3 are obtained.

Chlorine Compounds: TABLE 1

Com- Isomerism pound R5 R6 R7 R8 R1/R2 Flash point [° C.] or [α]_(D) 1 HH H H CH₃ 169-171 racemate 2 H H H H CH₃ 198 −173.3 3 H H H H CH₃ 199(+)-form 4 F H H H CH₃ 189-192 racemate 5 F H H H CH₃ 189-192 −89.1 6 FH H H CH₃ 220-223 +78.2 7 H F H H CH₃ 208-209 racemate 8 H F H H CH₃ 179−77.1 9 H F H H CH₃ 181-182 +74.6 10 H H H F CH₃ 222-224 racemate 11 H HH F CH₃ 232-235 −110.0 12 H H H F CH₃ 230-233 +106.0 13 Cl H H H CH₃228-230 racemate 14 Cl H H H CH₃ 252-254 −32.8 15 Cl H H H CH₃ 255-256+29.3 16 H Cl H H CH₃ 249-253 racemate 17 H Cl H H CH₃ 253-255 −126.2 18H Cl H H CH₃ 252-256 (+)-form 19 H H Cl H CH₃ 210-211 −96.7 20 H H Cl HCH₃ 208-209 100.8 21 H Br H H CH₃ 155-157 racemate 22 H Br H H CH₃151-152 −16.6 23 H Br H H CH₃ 150-155 (+)-form 24 OH H H H CH₃ 235-241−75.3 25 OH H H H CH₃ 236-240 +76.0

Flourine Compounds: TABLE 2

Com- Isomerism pound R5 R6 R7 R8 R1/R2 Flash point [° C.] or [α]_(D) 26H H H H CH₃ 220 −85.5 27 H H H H CH₃ 227 (+)-form 28 F H H H CH₃ 204racemate 29 F H H H CH₃ 204-205 −90.3 30 F H H H CH₃ 204-205 +83.0 31 HF H H CH₃ 175-176 −83.8 32 H F H H CH₃ 176-177 (+)-form 33 H H F H CH₃174 −81.5 34 H H F H CH₃ 174-176 (+)-form 35 H H H F CH₃ 205-210racemate 36 H H H F CH₃ 230-240 −71.3 37 H H H F CH₃ 240-245 (+)-form 38F H F H CH₃ 209 racemate 39 Cl H H H CH₃ 189-192 −64.0 40 Cl H H H CH₃184-187 (+)-form 41 H Cl H H CH₃ 239-141 racemate 42 H Cl H H CH₃210-215 −67.7 43 H Cl H H CH₃ 198-199 (+)-form 44 OCH3 H H H CH₃ 197-200racemate

Bromine Compounds: TABLE 3

Com- Flash pound R5 R6 R7 R8 R1/R2 point [° C.] Isomerism or [α]_(D) 45H H H H CH₃ 186-191 racemate 46 H H H H CH₃ 209-211 −65.0 47 H H H H CH₃205-207 +66.0

EXAMPLE 45-[4-(5-Fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]phthalide

Precursors

2-(3-Fluorophenyl)-2-methylpropionitrile

Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionitrile,2-(3-fluorophenyl)-2-methylpropionitrile is synthesized, boiling point102-103° C./0.029 hPa.

2-(3-Fluorophenyl)-2-methylpropionaldehyde

Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,2-(3-fluorophenyl)-2-methylpropionaldehyde, boiling point 120° C./0.04hPa, is obtained.

4-(3-Fluorophenyl)-4-methyl-2-oxovaleric acid

Analogously to the process that is described for4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid,4-(3-fluorophenyl)-4-methyl-2-oxovaleric acid is obtained as an oil.

4-(3-Fluorophenyl)-4-methyl-2-oxovaleric acid-ethyl ester

5.6 g of 4-(3-fluorophenyl)-4-methyl-2-oxovaleric acid and 0.197 ml ofsulfuric acid in 150 ml of ethanol are refluxed for 3 hours. The solventis distilled off. The residue is taken up in ethyl acetate, washed withsaturated sodium bicarbonate solution, dried (Na₂SO₄) and concentratedby evaporation. After bulb tube distillation, 5.6 g of4-(3-fluorophenyl)-4-methyl-2-oxovaleric acid-ethyl ester with a boilingpoint of 130° C./0.04 hPA is obtained.

4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleric acidethyl ester

5.3 g of 4-(3-fluorophenyl)-4-methyl-2-oxovaleric acid-ethyl ester in 60ml of dimethylformamide is combined at 0° C. with 3.25 g of cesiumcarbonate and 4.63 ml of trifluoromethyl(trimethyl)-silane. After 1 hourat 0° C. and 16 hours at room temperature, it is cooled again to 0° C.and mixed with 20 ml of a 1 M tetrabutylammonium fluoride solution intetrahydrofuran. After 30 minutes at 0° C., 2N sulfuric acid and ethylacetate are added to it, the ethyl acetate phase is washed with water,dried (Na₂SO₄) and concentrated by evaporation. After chromatography onsilica gel hexane-ethyl acetate (20:1) and bulb tube distillation, 4.45g of 4-(3-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid-ethyl ester is obtained (boiling point 100° C./0.04 hPa).

4-(5-Fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid ethyl ester4-(3-Fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid ethyl ester

3.3 g of 4-(3-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid ethyl ester is dissolved in 20 ml of trifluoroacetic acid and mixedat 0° C. with 0.84 ml of 100% nitric acid. After 3 hours at 0° C. and 16hours at room temperature, the batch is poured onto ice, thecrystallizate is suctioned off, washed with water and dried. Byrecrystallization from hexane, 2.5 g of4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid-ethyl ester with a flash point of 66-67° C. is obtained.

From the mother liquor, after chromatography on silica gel withhexane-ethyl acetate (8:1), another 500 mg of4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid-ethyl ester accumulates as a first fraction, and 800 mg of4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid-ethyl ester as an oil accumulates as a second fraction.

4-(5-Fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid

2.4 g of4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid-ethyl ester is dissolved in 30 ml of ethanol and purified with 60ml of 1 M sodium hydroxide solution. After 2 days at room temperature,it is concentrated by evaporation, the residue is dissolved in water,acidified at 0° C. and extracted with ethyl acetate. The ethyl acetatephase is washed neutral with water, dried (Na₂SO₄) and concentrated byevaporation. After crystallization from diisopropyl ether,4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid with a flash point of 130-131° C. is obtained.

5-[4-(5-Fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide

255 mg of4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid in 3 ml of dimethyl acetamide is mixed at 0° C. with 0.105 ml ofthionyl chloride, stirred for 30 minutes at 0° C. and 45 minutes at roomtemperature and combined with 300 mg of 5-aminophthalide. After 16 hoursat room temperature, it is mixed with 2 M hydrochloric acid and ethylacetate, the organic phase is washed neutral with water, dried (Na₂SO₄)and concentrated by evaporation. After chromatography on silica gel withhexane-ethyl acetate (3:2) and recrystallization from diisopropyl ether,80 mg of5-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalideis obtained, flash point 200-201° C.

6-[4-(5-Fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

is obtained analogously to Example 4 from4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid and 6-amino-2,3-benzoxazin-1-one, flash point 208-210° C.

EXAMPLE 65-[4-(3-Fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]phthalide4-(3-Fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid

is obtained from4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid-ethyl ester as an oil as described under Example 4 for4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid.

5-[4-(3-Fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]phthalide

is obtained analogously to Example 4 from4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid and 5-aminophthalide, flash point 188-189° C.

EXAMPLE 76-[4-(3-Fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

is obtained analogously to Example 4 from4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid and 6-amino-2,3-benzoxazin-1-one, flash point 236-237° C.

EXAMPLE 86-[4-(2-Bromo-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one

Precursors:

3-Methyl-2-butenoic acid-(4-fluorophenyl)amide

A solution of 10.0 g (0.1 mol) of 3-methyl-2-butenoic acid in 200 ml ofTHF is mixed with 9.4 ml (0.1 mol) of ethyl chloroformate and 14.1 ml(0.1 mol) of triethylamine at 0° C. After 10 minutes at roomtemperature, 10.6 ml (0.11 mol) of 4-fluoroaniline is added to it. Thebatch is stirred for 1 hour at room temperature, diluted with water andextracted with ethyl acetate (11). The organic phase is washed withsaturated NaCl, dried (Na₂SO₄) and concentrated by evaporation in avacuum. The residue is purified by column chromatography on silica gelwith hexane-ethyl acetate. Yield 18.8 g.

¹H-NMR (CDCl₃), δ (ppm) 1.92 (d, 3H), 2.25 (d, 3H), 5.71 (sept, 1H),7.02 (t, 2H), 7.13 (br., 1H), 7.50 (br., 2H).

3,4-Dihydro-4,4-dimethyl-6-fluoro-2-quinolone

9.4 g (48.7 mmol) of 3-methyl-2-butenoic acid-(4-fluorophenyl)amide isheated to 130-140° C. and mixed in portions with 9.6 g (73.5 mmol) ofaluminum trichloride. After the addition is completed, the temperatureis kept at 80° C. for 30 more minutes. It is allowed to cool to roomtemperature and carefully treated with 60 ml of ice water. After 15.0 mlof chloroform is added, the batch is stirred for 15 minutes, acidifiedwith dilute hydrochloric acid and extracted with chloroform (3×150 ml).The combined organic extracts are washed with saturated NaCl, dried(Na₂SO₄) and concentrated by evaporation in a vacuum. Columnchromatography on silica gel with hexane-ethyl acetate yields 6.0 g.

¹H-NMR (CDCl₃), δ (ppm)=1.34 (s, 6H), 2.48 (s, 2H), 6.80 (dd, 1H), 6.88(td, 1H), 7.02 (dd, 1H), 9.02 (br., 1H).

1-tert-Butoxycarbonyl-3,4-dihydro-4,4-dimethyl-6-fluoro-2-quinolone

A solution of 6.0 g (30.9 mmol) of3,4-dihydro-4,4-dimethyl-6-fluoro-2-quinolone in 200 ml of THF is mixedwith 8.8 g (40.2 mmol) of di-tert-butyldicarbonate and 4.9 g (40.2 mmol)of DMAP. After 24 hours at room temperature, it is concentrated byevaporation, and the residue is purified by column chromatography onsilica gel with hexane-ethyl acetate. Yield: 9.0 g.

¹H-NMR (CDCl₃), δ (ppm)=1.34 (s, 6H), 1.61 (s, 9H), 2.50 (s, 2H), 6.91(m, 2H), 7.03 (dd, 1H).

3-(2-tert-Butoxycarbonylamino-5-fluorophenyl)-3-methyl-1-butanol

375 ml (0.75 mol) of an aqueous 2 M lithium hydroxide solution is addedto a solution of 44 (0.15 mol) of1-tert-butoxycarbonyl-3,4-dihydro-4,4-dimethyl-6-fluoro-2-quinolone in 1l of THF. After 24 hours at room temperature, the batch is concentratedby evaporation, brought to pH 4 with 10% citric acid and extracted withether. The combined organic extracts are washed with saturated NaCl,dried (Na₂SO₄) and concentrated by evaporation in a vacuum. Columnchromatography of the residue on silica gel with hexane-ethyl acetateyields 34.0 g of3-(2-tert-butoxycarbonylamino-5-fluorophenyl)-3-methylbutyric acid[¹H-NMR (CDCl₃), δ (ppm)=1.62 (br.s, 15H), 2.77 (s, 2H), 6.41 (br, 1H),6.93 (td, 1H), 7.07 (dd, 1H), 7.20 (br, 1H)], which dissolves in 11 ofTHF and is mixed at 0° C. with 17 ml (121 mmol) of triethylamine and11.5 ml (121 mmol) of ethyl chloroformate. After 10 minutes at 0° C.,20.7 g (546 mmol) of sodium borohydride is added to it, and 1 l of MeOHis slowly added in drops to it. The batch is stirred for another 30minutes at 0° C., concentrated by evaporation and diluted with ethylacetate. It is washed with saturated NaCl, dried on Na₂SO₄ and purifiedby column chromatography on silica gel with hexane-ethyl acetate. Yield:6.7 g.

¹H-NMR (CDCl₃), δ (ppm)=1.40 (s, 6H), 1.51 (s, 9H), 2.06 (t, 2H), 3.49(q, 2H), 6.32 (br.s, 1H), 6.91 (ddd, 1H), 7.05 (dd, 1H), 7.28 (br., 1H).

2,2-Dimethylpropionic acid-[3-(2-amino-5-fluorophenyl)-3-methyl]butylester

A solution of 6.7 g (22.7 mmol) of3-(2-tert-butoxycarbonylamino-5-fluorophenyl)-3-methyl-1-butanol in 200ml of pyridine is mixed at 0° C. with 5.6 ml of pivaloyl chloride. After24 hours at room temperature, water is added to it, and it is stirredfor 2 hours at room temperature. The batch is diluted with ethylacetate, washed with 10% citric acid, water, saturated NaHCO₃ andsaturated NaCl, dried (Na₂SO₄) and concentrated by evaporation in avacuum. Column chromatography on silica gel with hexane-ethyl acetateyields 9.0 g of 2,2-dimethylpropionicacid-[3-(2-tert-butoxycarbonylamino-5-fluorophenyl)-3-methyl]butylester. 6.1 g-(16 mmol) of it is dissolved in 100 ml of dichloromethaneand mixed with 30 ml of trifluoroacetic acid. After 30 minutes at roomtemperature, the batch is diluted with ethyl acetate, washed with water,saturated NaHCO₃ and saturated NaCl, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. Purification by column chromatography on silicagel with hexane-ethyl acetate yields 4.0 g of product.

¹H-NMR (CDCl₃), δ (ppm)=1.15 (s, 9H), 1.46 (s, 6H), 2.15 (t, 2H), 3.67(br, 2H), 3.92 (t, 2H), 6.57 (dd, 1H), 6.75 (ddd, 1H), 6.92 (dd, 1H).

2,2-Dimethylpropionic acid-[3-(2-bromo-5-fluorophenyl)-3-methyl]butylester

A solution of 1.9 g (8.5 mmol) of copper(II) bromide and 1.4 ml (7.0mmol) of tert-butyl nitrite in 10 ml of acetonitrile is heated to 65° C.and mixed within 10 minutes with a solution of 2.0 g (7.1 mmol) of2,2-dimethylpropionic acid-[3-(2-amino-5-fluorophenyl)-3-methyl]butylester in 10 ml of acetonitrile. After 5 minutes at 65° C., it is allowedto cool to room temperature, concentrated by evaporation, and theresidue is purified by column chromatography on silica gel withhexane-ethyl acetate: Yield 1.6 g.

¹H-NMR (CDCl₃), δ (ppm)=1.12 (s, 9H), 1.52 (s, 6H), 2.41 (t, 211), 3.88(t, 2H), 6.79 (ddd, 1H), 7.12 (dd, 1H), 7.53 (dd, 1H).

3-(2-Bromo-5-fluorophenyl)-3-methylbutanol

At −20° C., a solution of 1.97 g (5.7 mmol) of 2,2-dimethylpropionicacid-[3-(2-bromo-5-fluorophenyl)-3-methyl]butyl ester in 20 ml oftoluene is mixed with 11.9 ml (14.3 mmol) of a 1.2 M diisobutylaluminumhydride-toluene solution. After 30 minutes at −20° C., the batch iscooled to −70° C. and mixed with 4 ml of isopropanol and 6 ml of water.After 2 hours at room temperature, the batch is filtered, and thefiltrate is concentrated by evaporation in a vacuum. Columnchromatography on silica gel with hexane-ethyl acetate yields 1.25 g ofproduct.

¹H-NMR (CDCl₃), δ (ppm)=1.52 (s, 6H), 2.37 (t, 2H), 3.45 (q, 2H), 6.80(ddd, 1H), 7.12 (dd, 1H), 7.54 (dd, 1H).

2-[1-Benzoyl-3-(2-bromo-5-fluorophenyl)-3-methylbutyl]furan

A solution of 1.0 g (3.8 mmol) of3-(2-bromo-5-fluorophenyl)-3-methylbutanol in 24 ml of dichloromethaneis treated with 8.5 ml of DMSO, 2.66 ml (19.2 mmol) of triethylamine and1.23 g (7.7 mmol) of pyridine-sulfur trioxide complex. After 1 hour atroom temperature, the batch is mixed with 30 ml of saturated NH₄Cl, andafter 15 minutes, it is extracted with 400 ml of ether. The extract iswashed with saturated NaCl, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. The residue (1.1 g) is dissolved in 8 ml of THFand added at −70° C. within 30 minutes to a solution of 2-furyllithiumin 38 ml of THF, which is produced from 0.85 ml of furan (11.5 mmol) and7.7 ml (12.3 mmol) of a 1.6 M nBuLi-hexane solution according to A.Dondoni et al., J. Org Chem. 1997, 62, 5484. After 1.5 hours at −70° C.,the batch is poured into 50 ml of saturated NH₄Cl and extracted with 400ml of MTBE. The organic phase is dried (Na₂SO₄) and concentrated byevaporation in a vacuum. The residue (1.1 g) is dissolved in 40 ml ofpyridine and mixed first with 0.9 ml (7.7 mmol) of benzoyl chloride at0° C. After 2 hours at 0° C. and 2 hours at room temperature, 30 mg ofDMAP is added to it, and after another 2 hours at room temperature, afurther 0.9 ml (7.7 mmol) of benzoyl chloride. After 18 hours at roomtemperature, the batch is mixed with 3 ml of water and concentrated byevaporation in a vacuum. The residue is taken up in 400 ml of MTBE, andthe resulting solution is washed with 10% citric acid and saturatedNaCl, dried (Na₂SO₄) and concentrated by evaporation in a vacuum. Columnchromatography on silica gel with hexane-ethyl acetate yields 1.46 g ofproduct.

¹H-NMR (CDCl₃), δ (ppm)=1.52 (s, 3H), 1.58 (s, 3H), 2.53 (dd, 1H), 3.33(dd, 1H), 6.10 (dd, 1H), 6.26 (m, 2H), 6.49 (ddd, 1H), 6.97 (dd, 1H),7.34 (m, 4H), 7.48 (m, 1H), 7.81 (m, 2H).

2-Benzoyl-4-(2-bromo-5-fluorophenyl)-4-methylvaleric acid-methyl ester

A suspension of 10.9 g (50.8 mmol) of sodium periodate in 140 ml ofwater-acetonitrile-tetrachloromethane (4:2:1) is mixed with 45 mg (0.34mmol) of ruthenium(IV)oxide-hydrate. After 10 minutes, a solution of2-[1-benzoyl-3-(2-bromo-5-fluorophenyl)-3-methylbutyl]furan in 40 ml ofacetonitrile is added to it, it is stirred for another 10 minutes, andthe batch is poured into 400 ml of saturated Na₂SO₃. A pH of 5 is setwith 10% citric acid, and the batch is extracted with ethyl acetate. Thecombined extracts are dried (Na₂SO₄) and concentrated by evaporation ina vacuum. The residue is taken up in 8 ml of DMF and treated with 0.42ml (6.8 mmol) of methyl iodide and 2.21 g (6.8 mmol) of cesiumcarbonate. After 5 hours at room temperature, the batch is diluted with600 ml of MTBE, washed with 10% sulfuric acid and saturated NaCl, dried(Na₂SO₄) and concentrated by evaporation in a vacuum. Columnchromatography on silica gel with hexane-ethyl acetate yields 0.9 g ofproduct.

¹H-NMR (CDCl₃), δ (ppm)=1.58 (s, 3H), 1.62 (s, 3H), 2.55 (dd, 1H), 3.10(dd, 1H), 3.72 (s, 3H), 5.21 (dd, 1H), 6.58 (ddd, 1H), 7.03 (dd, 1H),7.35-7.47 (m, 3H), 7.55 (m, 1H), 7.83 (m, 2H).

4-(2-Bromo-5-fluorophenyl)-2-hydroxy-4-methylvaleric acid-methyl ester

A solution of 0.9 g (2.13 mmol) of2-benzoyl-4-(2-bromo-5-fluorophenyl)-4-methylvaleric acid-methyl esterin 50 ml of MeOH is mixed with 1.47 g (10.6 mmol) of potassium carbonateand stirred for 3 hours at room temperature. The batch is acidified (pH3) with 10% sulfuric acid, and it is extracted with ethyl acetate. Thecombined extracts are washed with saturated NaCl, dried (Na₂SO₄) andconcentrated by evaporation in a vacuum. The residue is taken up in 8 mlof DMF and stirred with 1.92 g (5.9 mmol) of cesium carbonate and 0.38ml (5.9 mmol) of methyl iodide for 3 hours at room temperature. Thebatch is mixed with 10% citric acid and extracted with MTBE. The organicphase is washed with saturated NaCl, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. Column chromatography on silica gel withhexane-ethyl acetate yields 250 mg of product.

H-NMR (CDCl₃), δ (ppm) 1.57 (s, 3H), 1.61 (s, 3H), 2.10 (dd, 1H), 2.51(d, 1H), 2.82 (dd, 1H), 3.74 (s, 3H), 3.96 (ddd, 1H), 6.81 (ddd, 1H),7.22 (dd, 1H), 7.55 (dd, 2H).

6-[4-(2-Bromo-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

663 mg (1.56 mol) of1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one(Dess-Martin-periodinane, cf. D. B. Dess, J. C. Martin, J. Am. Chem.Soc. 1991, 113, 7277) is added to a solution of 250 mg (0.78 mmol) of4-(2-bromo-5-fluorophenyl)-2-hydroxy-4-methylvaleric acid-methyl esterin 10 ml of dichloromethane. After 1.5 hours at room temperature, thebatch is diluted with 150 ml of MTBE, washed with a solution of 1.2 g ofNaHCO₃ and 4.0 g of Na₂SO₃ in 50 ml of water, saturated NaHCO₃ andsaturated NaCl, dried (Na₂SO₄) and concentrated by gel with hexane-ethylacetate yields 0.9 g of product.

¹H-NMR (CDCl₃), 6 (Ppm)=1.58 (s, 3H), 1.62 (s, 3H), 2.55 (dd, 1H), 3.10(dd, 1H), 3.72 (s, 3H), 5.21 (dd, 1H), 6.58 (ddd, H), 7.03 (dd, 1H),7.35-7.47 (m, 3H), 7.55 (m, 1H), 7.83 (m, 2H).

4-(2-Bromo-5-fluorophenyl)-2-hydroxy-4-methylvaleric acid-methyl ester

A solution of 0.9 g (2.13 mmol) of2-benzoyl-4-(2-bromo-5-fluorophenyl)-4-methylvaleric acid-methyl esterin 50 ml of MeOH is mixed with 1.47 g (10.6 mmol) of potassium carbonateand stirred for 3 hours at room temperature. The batch is acidified (pH3) with 10% sulfuric acid, and it is extracted with ethyl acetate. Thecombined extracts are washed with saturated NaCl, dried (Na₂SO₄) andconcentrated by evaporation in a vacuum. The residue is taken up in 8 mlof DMF and stirred with 1.92 g (5.9 mmol) of cesium carbonate and 0.38ml (5.9 mmol) of methyl iodide for 3 hours at room temperature. Thebatch is mixed with 10% citric acid and extracted with MTBE. The organicphase is washed with saturated NaCl, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. Column chromatography on silica gel withhexane-ethyl acetate yields 250 mg of product.

¹H-NMR (CDCl₃), δ (ppm)=1.57 (s, 3H), 1.61 (s, 3H), 2.10 (dd, 1H), 2.51(d, 1H), 2.82 (dd, 1H), 3.74 (s, 3H), 3.96 (ddd, 1H), 6.81 (ddd, 1H),7.22 (dd, 1H), 7.55 (dd, 2H).

6-[4-(2-Bromo-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

663 mg (1.56 mol) of1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one(Dess-Martin-periodinane, cf. D. B. Dess, J. C. Martin, J. Am. Chem.Soc. 1991, 113, 7277) is added to a solution of 250 mg (0.78 mmol) of4-(2-bromo-5-fluorophenyl)-2-hydroxy-4-methylvaleric acid-methyl esterin 10 ml of dichloromethane. After 1.5 hours at room temperature, thebatch is diluted with 150 ml of MTBE, washed with a solution of 1.2 g ofNaHCO₃ and 4.0 g of Na₂SO₃ in 50 ml of water, saturated NaHCO₃ andsaturated NaCl, dried (Na₂SO₄) and concentrated by evaporation in avacuum. The residue (250 mg) is taken up in 16 ml of THF-EtOH (1:1) andmixed with 3.9 ml (3.9 mmol) of a 1 M sodium hydroxide solution. After30 minutes, the batch is concentrated in a vacuum, diluted with 20 ml ofwater and washed with MTBE. The aqueous phase is acidified with 10%sulfuric acid (pH 2) and extracted with 100 ml of ethyl acetate and 100ml of dichloromethane. The combined extracts are dried (NaSO₄) andconcentrated by evaporation in a vacuum. 0.06 ml (0.92 mmol) of thionylchloride is added in drops at −6° C. to the solution of the residue (230mg) in 5 ml of dimethyl acetamide. After 20 minutes at −6° C., 201 mg(1.14 mmol) of 6-amino-4-methyl-2,3-benzoxazin-1-one is added to it. Thebatch is stirred for 15 hours at room temperature, acidified with 50 mlof 10% citric acid and shaken out with 150 ml of MTBE. The organic phaseis washed with saturated NaCl, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. Column chromatography on silica gel withhexane-ethyl acetate yields 290 mg of product.

¹H-NMR ([D₆]-DMSO), δ (ppm)=1.57 (s, 6H), −2.5 (s, 3H; under the DMSOsignal), 3.89 (s, 2H), 7.03 (ddd, 114), 7.34 (dd, 1H), 7.62 (dd, 1H),8.25 (d, 1H), 8.33 (m, 2H), 11.03 (br., 1H);

MS (Cl) m/z=461, 463 (M⁺).

6-[4-(2-Bromo-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

0.23 ml (1.25 mmol) of trifluoromethyl(trimethyl)silane and 256 mg (0.79mmol) of cesium carbonate are added at 0° C. to a solution of 290 mg(0.63 mmol) of6-[4-(2-bromo-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-onein 7 ml of DMF. After 24 hours, the same amount of silane and base areadded and stirred for another 24 hours at room temperature. The batch isdiluted with 150 ml of ethyl acetate, washed with water and saturatedNaCl, dried (Na₂SO₄) and concentrated by evaporation in a vacuum.Purification by column chromatography of the residue on silica gelyields 230 mg of product.

¹H-NMR (CDCl₃), δ (ppm)=1.55 (s, 3H), 1.63 (s, 3H), 2.58 (s, 3H), 3.10(br. s, 1H), 6.63 (ddd, 1H), 7.11 (dd, 1H), 7.40 (dd, 1H), 7.62 (dd,1H), 8.14 (d, 1H), 8.33 (d, 1H), 8.52 (br.s, 1H);

MS (CI) m/z=531, 533 (M+).

EXAMPLE 96-[4-(Indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

Precursors:

4-(1-Hydroxy-1-methylethyl)indan

10 ml (14 mmol) of a 1.4 M methylmagnesium bromide solution intoluene-THF (3:1) is added in drops at 0° C. to a solution of 1.6 g (10mmol) of 4-acetylindan (F. Dallacker, J. Van Wersch, Chem. Ber. 1972,105, 2565) in 40 ml of THF. After 30 minutes at 0° C. and 1.5 hours atroom temperature, the batch is diluted with 200 ml of ethyl acetate,washed with 1 M hydrochloric acid and saturated NaCl, dried (Na₂SO₄) andconcentrated by evaporation in a vacuum. Column chromatography of theresidue on silica gel with hexane-ethyl acetate yields 0.64 g ofproduct.

¹H-NMR (CDCl₃), δ (ppm)=1.64 (s, 6H), 1.74 (s, 1H), 2.07 (pent, 2H),2.90 (t, 2H), 3.16 (t, 2H), 7.11-7.19 (m, 2H), 7.29 (m, 1H).

6-[4-(Indan-4′-yl)-4-methyl-2-oxovaleric acid

0.63 g (3.4 mmol) of 4-(1-hydroxy-1-methylethyl)indan is introduced with0.96 g (5.1 mmol) of 2-trimethylsiloxyacrylic acid-ethyl ester (H.Sugimura, K. Yoshida, Bull. Chem. Soc. Jpn. 1992, 65, 3209) into 20 mlof dichloromethane and treated at −70° C. with 0.31 ml (2.6 mmol) oftin(IV) chloride. After 20 minutes at −70° C., the batch is poured intosemiconcentrated potassium carbonate solution and extracted with ethylacetate. The combined extracts are washed with saturated NaCl, dried(Na₂SO₄) and concentrated by evaporation in a vacuum. 0.89 g of an oil,which is dissolved in 30 ml of EtOH-THF (2:1) and is reacted with 12.8ml (12.8 mmol) of 1 M NaOH, is obtained. After 2 hours at roomtemperature, the batch is concentrated by evaporation in a vacuum, andthe residue is taken up in 30 ml of water. The aqueous phase is washedwith ether and acidified with 50 ml of 1 M hydrochloric acid. Extractionwith ethyl acetate, drying (Na₂SO₄) and concentration by evaporationyields 0.64 g of acid.

¹H-NMR (CDCl₃), δ (ppm)=1.52 (s, 6H), 2.07 (pent, 2H), 2.85 (t, 2H),3.08 (t, 2H), 3.42 (s, 2H), 5.02 (br.), 7.04-7.17 (m, 3H).

6-[4-(Indan-4′-yl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

0.63 g (2.6 mmol) of 6-[4-(indan-4′-yl)-4-methyl-2-oxovaleric acid and0.69 g (3.9 mmol) of 6-amino-4-methyl-2,3-benzoxazin-1-one are convertedinto 0.31 g of product as described in Example 1.

¹H-NMR (CDCl₃), δ (ppm)=1.56 (s, 6H), 2.08 (pent, 2H), 2.59 (s, 3H),2.83 (t, 2H), 3.12 (t, 2H), 3.52 (s, 2H), 7.07-7.17 (m, 3H), 7.72 (dd,1H), 8.20 (d, 1H), 8.36 (d, 1H), 8.87 (br. s, 1H).

6-[4-(Indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

In a way similar to the instructions of Example 1, 0.31 g (0.77 mmol) of6-[4-(indan-4′-yl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis reacted with 0.56 ml (3.1 mol) of trifluoromethyl(trimethyl)silaneand 626 mg (1.9 mmol) of cesium carbonate in 9 ml of DMF. After columnchromatography on silica gel with hexane-ethyl acetate, 90 mg of productis obtained.

¹H-NMR (CDCl₃), δ (ppm)=1.47 (s, 3H), 1.49 (s, 3H), 2.11 (m, 2H), 2.62(s, 3H), 2.76-2.92 (m, 4H), 2.96 (s, 1H), 3.17 (t, 2H), 7.14 (m, 4H),7.63 (dd, 1H), 8.28 (d, 1H), 8.35 (d, 1H), 8.88 (br. s, 1H);

MS (CI) m/z=475 (MH⁺).

Separation of Enantiomers of Example 9:

The enantiomer mixture of Example 9 is separated by chromatography onchiral support medium (CHIRALPAK AD®, DAICEL Company) withhexane/ethanol (95:5, vv). Thus obtained from 830 mg of racemate are:

-   (−)    6-[4-(Indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one    as a first fraction: 310 mg, [MS (Cl) m/z=475 (MH⁺), α_(D)=−55.7    (c=0.5 in tetrahydrofuran)] and-   (+)    6-[4-(Indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one    as a second fraction: 280 mg, [Flash point 196-197° C., α_(D)=+55.7°    (c=0.5 in tetrahydrofuran)]

EXAMPLE 106-[4-(5-Fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one2-Benzoyl-4-(5-fluoro-2-vinylphenyl)-4-methylvaleric acid-methyl ester

A solution of 0.53 g (1.25 mmol) of2-benzoyl-4-(2-bromo-5-fluorophenyl)-4-methylvaleric acid-methyl esterand 77 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium in 40 mlof toluene is refluxed with vinyl(tributyl)stannane for 8 hours. Then,it is concentrated by evaporation and purified by column chromatographyon silica gel with hexane-ethyl acetate: 320 mg of product.

¹H-NMR (CDCl₃), δ (ppm)=1.51 (s, 3H), 1.55 (s, 3H), 2.44 (dd, 1H), 2.66(dd, 1H), 3.70 (s, 3H), 5.14 (dd, 1H), 5.33 (dd, 1H), 5.43 (dd, 1H),6.77 (td, 1H), 6.97 (dd, 1H), 7.22-7.33 (m, 2H), 7.48 (m, 2H), 7.55 (m,1H), 7.80 (d, 2H).

4-(5-Fluoro-2-vinylphenyl)-2-hydroxy-4-methylvaleric acid-methyl ester

Produced analogously to Example 8.

¹H-NMR (CDCl₃), δ (ppm)=1.48 (s, 3H), 1.53 (s, 3H), 1.98 (dd, 1H), 2.46(dd, 1H), 2.50 (d, 1H), 3.70 (s, 3H), 3.96 (ddd, 1H), 5.28 (dd, 1H),5.41 (dd, 1H), 6.90 (td, 1H), 7.12 (dd, 1H), 7.25 (dd, 1H), 7.33 (dd,1H).

6-[4-(5-Fluoro-2-vinylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

Produced analogously to Example 8.

¹H-NMR (CDCl₃), δ (ppm)=1.56 (s, 6H), 2.58 (s, 3H), 3.65 (s, 2H), 5.28(dd, 1H), 5.34 (dd, 1H), 6.91 (td, 1H), 7.13 (dd, 1H), 7.20-7.30 (m,2H), 7.78 (dd, 1H), 8.22 (d, 1H), 8.35 (d, 1H), 8.98 (br., 1H).

6-[4-(5-Fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

Produced analogously to Example 8.

H-NMR (CDCl₃), δ (ppm)=1.47 (s, 3H), 1.54 (s, 3H), 2.60 (s, 3H), 2.87(m, 3H), 5.45 (dd, 1H), 5.50 (dd, 1H), 6.85 (td, 1H), 7.06 (dd, 1H),7.25-7.37 (m, 2H), 7.67 (dd, 1H), 8.18 (d, 1H), 8.34 (d, 1H), 8.73(br.s, 1H);

MS (ES+) m/z 479 (MH⁺).

EXAMPLE 116-[2-Hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one2-Methyl-2-(4-trifluomethylphenyl)propionitrile

A solution of 6.80 g (41.4 mmol) of 4-fluorobenzotrifluoride in 250 n oftoluene is mixed at 0° C. with 124 ml (62 mmol) of a 0.5 M potassiumhexamethyldisilazide-THF solution and 9.44 g (137 mmol) of isobutyricacid nitrile. The batch is stirred for 4 hours at 60° C. and dilutedafter cooling with water and ethyl acetate. The organic phase isseparated, washed with 10% H₂SO₄ and saturated NaCl, dried (Na₂SO₄) andconcentrated by evaporation in a vacuum.

Column chromatography on silica gel with hexane-ethyl acetate yields7.68 g of product.

¹H-NMR (CDCl₃), δ (ppm)=1.76 (s, 6H), 7.62 (d, 2H), 7.68 (d, 2H).

4-Methyl-4-(4-trifluomethylphenyl)-2-pentenoic acid-ethyl ester

A solution of 7.6 g (36 mmol) of2-methyl-2-(4-trifluomethylphenyl)propionitrile in 250 ml of toluene ismixed at −70° C. with 57 ml (68 mmol) of a 1.2 M diisobutylaluminumhydride-toluene solution. After 1 hour at −70° C., 10% tartaric acid isadded in drops to it, and it is stirred for 15 minutes at roomtemperature. The batch is diluted with ether, the organic phase isseparated and washed with saturated NaCl, dried (Na₂SO₄) andconcentrated by evaporation in a vacuum: 7.96 g of crude2-methyl-2-(4-trifluoromethylphenyl)propionaldehyde. 2.05 g (9.25 mmol)thereof is dissolved in 6 ml of DME and added in drops to a solutionthat was prepared from 3.10 g (13.9 mmol) of phosphonoaceticacid-triethyl ester and 0.55 g (13.9 mmol) of 60% sodium hydride in 12ml of DME. After 1 hour at room temperature, the batch is mixed withsaturated NH₄Cl and diluted with ethyl acetate and water. The phases areseparated, the aqueous phase is extracted with ethyl acetate, and thecombined organic extracts are washed with saturated NaCl, dried (Na₂SO₄)and concentrated by evaporation in a vacuum. The residue is purified onsilica gel with hexane-ethyl acetate: 1.72 g of product.

¹H-NMR (CDCl₃), δ (ppm)=1.30 (t, 3H), 1.49 (s, 6H), 4.21 (q, 2H), 5.82(d, 1H), 7.10 (d, 1H), 7.43 (d, 2H), 7.59 (d, 2H).

2-Hydroxy-4-methyl-4-(4-trifluoromethylphenyl)valeric acid-ethyl ester

1.72 g (6.0 mmol) of 4-methyl-4-(4-trifluomethylphenyl)-2-pentenoicacid-ethyl ester is stirred in ethyl acetate in the presence of 0.17 gof 10% palladium/activated carbon catalyst for 15 hours in a hydrogenatmosphere (1 atm). The batch is filtered on Celite and concentrated byevaporation in a vacuum: 1.72 g of4-methyl-4-(4-trifluomethylphenyl)valeric acid-ethyl ester. 0.57 g (2.0mmol) thereof is dissolved in 7 ml of THF and treated at −78° C. with5.6 ml (2.8 mmol) of potassium hexamethyldisilazide-toluene solution.After 25 minutes. 0.73 g (2.8 mmol) of3-phenyl-2-phenylsulfonyloxaziridine (F. A. Davis. S. Chattopadhyay, J.C. Towson, S. Lal, T. Reddy J. Org. Chem. 1988, 53, 2087) in 7 ml of THFis added in drops to it and stirred for 30 minutes at −78° C. The batchis mixed with saturated NH₄Cl and heated within 1 hour to roomtemperature. THF is removed in a vacuum, the residue is taken up inether, the solid is filtered off, the phases are separated, and theaqueous phase is extracted with ether. The combined organic extracts arewashed with saturated NaCl, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. Column chromatography on silica gel withhexane-ethyl acetate yields 0.14 g of product.

¹H-NMR (CDCl₃), δ (ppm)=1.26 (t, 3H), 1.42 (s, 3H), 1.50 (s, 3H), 1.90(dd, 1H), 2.10 (br., 1H), 2.24 (dd, 1H), 3.94 (dd, 1H), 4.15 (m, 2H),7.53 (d, 2H), 7.60 (d, 2H).

6-[4-Methyl-2-oxo-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

Produced analogously to Example 8.

¹H-NMR (CDCl₃), δ (ppm)=1.53 (s, 6H), 2.58 (s, 3H), 3.47 (s, 2H), 7.50(d, 2H), 7.58 (d, 2H), 7.78 (dd, 1H), 8.21 (d, 1H), 8.35 (d, 1H), 8.98(br., 1H);

MS (Cl) m/z=433 (MH⁺).

6-[2-Hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroyl-amino]-4methyl-2,3-benzoxazin-1-one

Produced analogously to Example 8.

¹H-NMR (CDCl₃), δ (ppm)=1.47 (s, 3H), 1.50 (s, 3H), 2.53 (d, 1H), 2.58(s, 3H), 2.91 (s, 1H), 2.95 (d, 1H), 7.55 (s, 4H), 7.62 (dd, 1H), 8.18(d, 1H), 8.33 (d, 1H), 8.73 (br.s, 1H);

MS (ES+) m/z=503 (MH⁺).

EXAMPLE 126-[4-(2-Bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4methyl-2,3-benzoxazin-1-one

Produced analogously to Example 8.

¹H-NMR-(CDCl₃), δ (ppm)=1.56 (s, 3H), 1.64 (s, 3H), 2.58 (s, 3H), 3.00(d, 1H), 3.22 (d, 1H), 3.31 (br. s, 1H), 6.58 (td, 1H), 6.97 (dt, 1H),7.64 (dd, 1H), 8.11 (d, 1H), 8.34 (d, 1H), 8.43 (br.s, 1H).

EXAMPLE 136-[4-(3,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

Example 13 accumulates as by-product in the synthesis of Example 12.

¹H-NMR (CDCl₃), δ (ppm)=1.41 (s, 3H), 1.44 (s, 3H), 2.44 (d, 1H), 2.60(s, 3H), 2.80 (br. s, 1H), 2.89 (d, 1H), 6.53 (tt, 1H), 6.92 (m, 2H),7.66 (dd, 1H), 8.24 (d, 1H), 8.35 (d, 1H), 8.70 (br.s, 1H).

EXAMPLE 146-[4-(5-Fluoro-2-trifluoromethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one2-(5-Fluoro-2-trifluoromethylphenyl)-acetonitrile

1.95 g (30 mmol) of potassium cyanide is added to a solution of 5.14 g(20 mmol) of 5-fluoro-2-trifluoromethylbenzyl bromide in 45 ml ofethanol/8 ml of water, and it is stirred for 64 hours at roomtemperature. The reaction solution is diluted with ethyl acetate andextracted with saturated sodium bicarbonate solution. The organic phaseis washed with water, dried and concentrated by evaporation. Theremaining residue is purified by bulb tube distillation andrecrystallized. Yield: 3.6 g (89%).

Flash point 41-42° C.

2-(5-Fluoro-2-trifluoromethylphenyl)-2-methyl-propionitrile

Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionitrile,2-(5-fluoro-2-trifluoromethylphenyl)-2-methyl-propionitrile is obtainedas a colorless oil, boiling point 90° C./0.04 hPa.

2-(5-Fluoro-2-trifluoromethylphenyl)-2-methyl-propionaldehyde

Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,2-(5-fluoro-2-trifluoromethylphenyl)-2-methyl-propionaldehyde isobtained as a colorless oil, boiling point 80° C./0.05 hPa.

4-(5-Fluoro-2-trifluoromethylphenyl)-4-methyl-oxovaleric acid

Analogously to the process that is described for4-(5-fluoro-2-methylphenyl)-4-methyl-oxovaleric acid,4-(5-fluoro-2-trifluoromethylphenyl)-4-methyl-oxovaleric acid isobtained as a viscous oil.

6-[4-(5-Fluoro-2-trifluoromethylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-[4-(5-fluoro-2-trifluoromethylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis synthesized.

¹H-NMR (CDCl₃+DMSO), δ (ppm)=1.47 (s, 6H), 2.44 (s, 3H), 3.59 (s, 2H),6.92 (dt, 1H), 7.33 (dd, 1H), 7.61 (dd, 1H), 8.03 (dd, 1H), 8.16 (d,1H), 8.30 (d, 1H), 10.34 (bs, 1H).

6-[4-(5-Fluoro-2-trifluoromethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-[4-(5-fluoro-2-trifluoromethylphenyl]-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis synthesized.

¹H-NMR (CDCl₃), δ (ppm)=1.42 (s, 3H), 1.55 (s, 3H), 2.56 (d, 1H), 2.57(s, 3H), 2.91 (d, 1H), 3.28 (bs, 1H), 6.85 (dt, 1H), 7.32 (dd, 1H),7.56-7.66 (m, 2H), 8.13 (d, 1H), 8.34 (d, 1H), 8.51 (bs, 1H);

MS (El) m/z=520 (M⁺).

Separation of the Enantiomers of Example 14:

The enantiomer mixture of Example 14 is separated by chromatography onchiral support medium (CHIRALPAK AD®, DAICEL Company) withhexane/ethanol (19:1, vv). Thus obtained from 100 mg of racemate are:

-   (−)-6-[4-(5-Fluoro-2-trifluoromethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one    as a first fraction: 40 mg, [flash point 162-165° C., α_(D)=−45.5°    (c 0.5 in tetrahydrofuran)] and-   (+)-6-[4-(5-Fluoro-2-trifluoromethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one    as a second fraction: 38 mg, [flash point 160-165° C.]

Analogously to Example 14, the compounds of Table 4 are obtained.

Trifluoromethyl Compounds: TABLE 4

Com- Flash pound R5 R6 R7 R8 R1/R2 point [° C.] Isomerism or [α]_(D) 1 HH H H CH₃ 154-156 racemate 2 H H H H CH₃ 164-170 −72.8 3 H H H H CH₃188-190 +69.0 4 H F H H CH₃ 170-172 racemate 5 H F H H CH₃ 173-175 −67.56 H F H H CH₃ 174-177 (+)-form 7 H H F H CH₃ 170 racemate 8 H H F H CH₃162-166 −45.5 9 H H F H CH₃ 160-165 (+)-form 10 H H Cl H CH₃ 172racemate 11 H H Cl H CH₃ 178-181 −143.1 12 H H Cl H CH₃ 180-182 (+)-form

EXAMPLE 156-[2-Hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one2-Methyl-2-(1-naphthyl)-propionitrile

A solution of 16.7 g (100 mmol) of 1-naphthylacetonitrile in 200 m ofDMF and 15 ml (240 mmol) of methyl iodide is mixed at 0° C. with 10.4 g(260 mmol) of sodium hydride (addition within 2.5 hours). The batch isstirred for 3 hours at 0° C. and for 18 hours at 25° C. It is mixed withice and ethyl acetate. The organic phase is acidified with 10% H₂SO₄,washed three times with water, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. A large-scale purification is carried out bybulb tube distillation (boiling range 60-130° C.) in an oil pump vacuum;yield: 18.8 g.

¹H-NMR (CDCl₃), δ (ppm)=2.00 (s, 6H), 7.41-7.60 (m, 3H), 7.64 (ddd, 1H),7.87 (d br., 1H), 7.93 (dd, 1H), 8.55 (d, 1H).

4-Methyl-4-(1-naphthyl)-2-pentenoic acid-ethyl ester

Analogously to the production of4-methyl-4-(4-trifluomethylphenyl)-2-pentenoic acid-ethyl ester ofExample 11, 7.62 g of the product is obtained from 8.81 g (45.1 mmol) of2-methyl-2-(1-naphthyl)-propionitrile.

¹H-NMR (CDCl₃), δ (ppm)=1.25 (t, 3H), 1.70 (s, 6H), 4.16 (q, 2H), 5.73(d, 1H), 7.38-7.50 (m, 4H), 7.53 (dd, 1H), 7.78 (d, 1H), 7.81-7.89 (m,1H), 8.00-8.08 (m, 1H).

2-Hydroxy-4-methyl-4-(1-naphthyl)-valeric acid-ethyl ester

Analogously to the production of2-hydroxy-4-methyl-4-(4-trifluomethylphenyl)-valeric acid-ethyl ester ofExample 11, 3.52 g of the product is obtained from 7.62 g (28.4 mmol) of4-methyl-4-(1-naphthyl)-2-pentenoic acid-ethyl ester.

¹H-NMR (CDCl₃), δ (ppm)=1.14 (t, 3H), 1.72 (s, 3H), 1.74 (s, 3H), 2.27(dd, 1H), 2.52 (dd, 1H), 2.76 (dd, 1H), 3.95-4.08 (m, 3H), 7.38-7.51 (m,3H), 7.57 (d, 1H), 7.75 (d, 1H), 7.88 (dd, 1H), 8.40 (d, 1H).

6-[4-Methyl-2-oxo-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

Produced analogously to Example 11. 861 mg of the product is obtained.

¹H-NMR (CDCl₃), δ (ppm)=1.59 (s, 3H), 1.78 (s, 6H), 2.57 (s, 3H), 3.88(s, 2H), 7.44 (m, 2H), 7.54 (m, 2H), 7.69 (dd, 1H), 7.75 (d br., 1H),7.87 (dd, 1H), 8.15 (d, 1H), 8.32 (d, 1H), 8.46 (d br., 1H).

6-[2-Hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

Produced analogously to Example 8. 77.1 mg of the product is obtained.

¹H-NMR (CDCl₃), δ (ppm)=1.57 (s, 3H), 1.67 (s, 3H), 1.78 (s, 3H), 2.54(s, 2H), 3.10 (d, 1H), 3.23 (d, 1H), 5.30 (s, 2H), 7.25-7.38 (m, 2H),7.46 (dd, 1H), 7.51 (d, 1H), 7.60 (m, 214), 7.76 (d, 1H), 7.97 (d br.,1H), 8.24 (d, 1H), 8.42 (d, 1H).

EXAMPLE 166-[3-{1-(2-Chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

Precursors:

1-(2-Chlorophenyl)-cyclopropane-carbon itrile

A solution of 13.1 g of 2-chlorophenylacetonitrile and 20.3 g of1,2-dibromopropane in 142 ml of DMF is mixed with 9 g of sodium hydride(55-65% in oil] at room temperature. It is stirred for several hours andcarefully added to water. After extraction with ethyl acetate andfiltration by silica gel, the desired product is obtained: 13.1 g

MS (ei): M⁽⁺⁾=177

1-(2-Chlorophenyl)-1-cyclopropanecarbaldehyde

131. g of (1-(2-chlorophenyl)-1-cyclopropane carbaldehyde in 116 ml oftoluene is mixed at −70° C. drop by drop with 64.5 ml ofdiisobutylaluminum hydride. After 4 hours at −70° C., 343 ml of ethylacetate is added. It is allowed to come to room temperature overnight.Water and ethyl acetate are added, filtered on diatomaceous earth, ethylacetate solution is washed with water, dried (Na₂SO₄) and concentratedby evaporation. After flash chromatography on silica gel withhexane-ethyl acetate (8:2), 9.7 g of the product is obtained.

MS (ei): M⁽⁺⁾=180

2-Ethoxy-3-[1-(2-chlorophenyl)-1-cyclopropyl]-acrylic acid ethyl ester

14.3 g of phosphonate in 40 ml of tetrahydrofuran is mixed at 0° C. with29 ml of lithium diisopropylamide. It is stirred for 20 more minutes at0° C. 9.7 g of 1-(2-chlorophenyl)-1-cyclopropane carbaldehyde in 40 mlof tetrahydrofuran is added in drops. After 24 hours at roomtemperature, it is mixed with water, extracted with ethyl acetate, ethylacetate solution is washed with water and dried (Na₂SO₄). Afterconcentration by evaporation, 15.5 g of the product is obtained.

MS (ei): M⁽⁺⁾=294

2-Ethoxy-3-[1-(2-chlorophenyl)-1-cyclopropyl]-acrylic acid

15.4 g of 2-ethoxy-3-[1-(2-chlorophenyl)-1-cyclopropyl]-acrylic acidethyl ester in 350 ml of 1 M sodium hydroxide solution (ethanol-water2:1) is stirred for 24 hours at room temperature. Solvent is distilledoff, residue is distributed between water and diethyl ether, watersolution is acidified with 2N hydrochloric acid, and extracted withdiethyl ether. After the organic phase is washed with water, dried(Na2SO4) and concentrated by evaporation, 11.2 g of the product isobtained.

MS (ei): M⁽⁺⁾=266

3-[1-(2-Chlorophenyl)-1-cyclopropyl]-2-oxo-propionic acid

11.2 g of 2-ethoxy-3-[1-(2-chlorophenyl)-1-cyclopropyl]-acrylic acid isstirred in 230 ml of 1 M sulfuric acid and 42 ml of concentrated aceticacid for 24 hours at 110° C. Water is added, it is extracted with ethylacetate, and ethyl acetate solution is washed with water. After drying(Na2SO4) and concentration by evaporation, 10.7 g of the product isobtained.

MS (ei): M⁽⁺⁾=238

¹H-NMR (CDCl₃), a (ppm)=0.98 (m, 4H), 3.28 (s, 2H), 7.13-7.22 (m, 2H),7.29-7.35 (m, 1H), 7.43-7.49 (m, 1H)

6-{3-[1-(2-Chlorophenyl)-cyclopropyl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1-one

10.7 g of 3-[1-(2-chlorophenyl)-1-cyclopropyl]-2-oxopropionic acid in175 ml of dimethyl acetamide is mixed at −5° C. with 4.1 ml of thionylchloride, and it is stirred for 20 minutes. Then, 5.0 g of MBO is addedin solid form. After 20 hours at room temperature, water and ethylacetate are added, ethyl acetate solution is washed with water, dried(Na2SO4) and concentrated by evaporation. After chromatography on silicagel with hexane-ethyl acetate (0%-30%), 9.6 g of the product isobtained.

MS (ei): M⁽⁺⁾=397

6-{3-[1-(2-Chlorophenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one

9.5 g of6-{3-[1-(2-chlorophenyl)-cyclopropyl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1-onein 140 ml of dimethylformamide is mixed at 0° C. with 16.9 ml oftrifluoromethyl-trimethylsilane and 9.65 g of cesium carbonate. After 24hours at room temperature, a spatula tip full of tetrabutylammoniumfluoride hydrate is added, and it is stirred for 30 more minutes. It ismixed with water and ethyl acetate, ethyl acetate solution is washedwith water, dried (Na2SO4) and concentrated by evaporation. Afterchromatography on silica gel with hexane-ethyl acetate (0%-30%), 2.98 gof the product is obtained.

Flash point 195-196° C.

Separation of the Enantiomers of Example 16:

The enantiomer mixture of Example 16 is separated by chromatography onchiral support medium (CHIRALPAK AD®, DAICEL Company) withhexane/ethanol (19:1, vv). Thus obtained from 2.68 g of racemate are:

-   (−)-6-[3-{1-(2-Chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one    as a first fraction: 1.3 g, [flash point 233-235° C., α_(D)=−81.40    (c=0.5 in chloroform)] and-   (+)-6-[3-{1-(2-Chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one    as a second fraction: 1.25 g, [flash point 238-240° C.]

Analogously to Example 16, the compounds of Tables 5-8 are obtained.

Chlorine Compounds: TABLE 5

Com- pound R5 R6 R7 R8 n = Flash point [° C.] Isomerism or [α]_(D) 1 H HH H 2 231-233 −47.1 2 H H H H 2 230-232 (+)-form 3 H H H H 3 195-197−70.5 4 H H H H 3 202-203 (+)-form 5 H F H H 1 228-230 racemate 6 H F HH 1 218-219 −88.6 7 H F H H 1 217-219 (+)-form 8 H F H H 2 212-214racemate 9 H F H H 2 236-238 +74.2 10 H F H H 2 235-237 −75.0 11 H H F H1 196 racemate 12 H H F H 1 239-240 −95.4 13 H H F H 1 239-240 (+)-form14 H H F H 2 222-223 racemate 15 H H F H 2 247-249 77.6 16 H H F H 2247-249 +79.6 17 H Cl H H 1 235-239 −81.6 18 H Cl H H 1 199-201 (+)-form19 H Cl H H 2 232 −46.7 20 H Cl H H 2 232-234 (+)-form

Trifluoromethyl Compounds: TABLE 6

Com- pound R5 R6 R7 R8 n = Flash point [° C.] Isomerism or [α]_(D) 21 HH H H 1 205 racemate 22 H H H H 1 222-223 −96.5 23 H H H H 1 219-221(+)-form 24 H H H H 2 218-222 racemate 25 H H H H 2 220-221 −16.4 26 H HH H 2 220-222 (+)-form 27 H H H H 4 150-153 racemate 28 H H F H 1242-245 racemate 29 H H F H 1 235-246 −40.1 30 H H F H 1 244-246(+)-form 31 H H F H 2 241-244 racemate 32 H H F H 2 242-244 −82.7 33 H HF H 2 242-244 (+)-form

Fluorine Compounds: TABLE 7

Com- pound R5 R6 R7 R8 n = Flash point [° C.] Isomerism or [α]_(D) 34 HH H H 1 215-216 racemate 35 H H H H 1 260-262 −113.3 36 H H H H 1260-263 (+)-form 37 H H H H 2 190-191 racemate 38 H H H H 2 198-201−103.4 39 H H H H 2 207-209 +103 40 H H H H 3 168-171 −117.6 41 H H H H3 167-170 +112.3 42 H H H H 4 90-93 racemate 43 H H H H 4 178-184 −10544 H H H H 4 185-187 +102.6 45 F H H H 1 230-232 racemate 46 F H H H 1238-250 −106.3 47 F H H H 1 254-256 (+)-form 48 F H H H 2 182-185racemate 49 H H F H 1 198-199 racemate 50 H H F H 1 240 −130.2 51 H H FH 1 241 (+)-form 52 F H F H 1 215 racemate 53 F H F H 2 205 racemate

Bromine Compounds: TABLE 8

Com- pound R5 R6 R7 R8 n = Flash point [° C.] Isomerism or [α]_(D) 54 HH H H 1 196-200 racemate 55 H H H H 1 239-241 −56.6 56 H H H H 1 240-241+56.0

EXAMPLE 176-[2-Hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

Precursors:

2-Methyl-2-(3-methyl-2-nitrophenyl)-propionitrile

Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionitrile,2-methyl-2-(3-methyl-2-nitrophenyl)-propionitrile is synthesized,boiling point 140° C./0.05 hPa.

2-Methyl-2-(3-methyl-2-nitrophenyl)-propionaldehyde

Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,2-methyl-2-(3-methyl-2-nitrophenyl)-propionaldehyde, boiling point 140°C./0.05 hPa, is obtained.

4-Methyl-4-(3-methyl-2-nitrophenyl)-2-oxovaleric acid

Analogously to the process that is described for4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid,4-methyl-4-(3-methyl-2-nitrophenyl)-2-oxovaleric acid is obtained as anoil.

6-[4-Methyl-4-(3-methyl-2-nitrophenyl)-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

is obtained analogously to5-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]phthalidefrom 4-methyl-4-(3-methyl-2-nitrophenyl)-2-oxovaleric acid and6-amino-2,3-benzoxazin-1-one, flash point 184-187° C.

6-[2-Hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

was obtained analogously to Example 1 from6-[4-methyl-4-(3-methyl-2-nitrophenyl)-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one,flash point 201-203° C.

EXAMPLE 185-[4-(2-Amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino-phthalide

65.8 mg(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalidein 15 ml of methanol is reduced at normal pressure within 3 hours in thepresence of 20 mg of palladium/carbon (10%) with hydrogen, suctioned offon diatomaceous earth and concentrated by evaporation. Afterrecrystallization from ethyl acetate/diisopropyl ether, 51 mg of5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalideof flash point 174° C. is obtained.

EXAMPLE 196-[4-(2-Amino-5-fluorophenyl)-2-hydroxy-4-Methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one

42 mg of6-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis dissolved in 1 ml of acetic acid and 1 ml of tetrahydrofuran b, mixedwith 22.5 mg of iron powder and stirred for 16 hours at roomtemperature. It is suctioned off on diatomaceous earth, concentrated byevaporation, the residue is taken up in ethyl acetate and washed with asaturated sodium hydrogen carbon solution. After chromatography onsilica gel with hexane/ethyl acetate (1.5+1) and recrystallization fromdiisopropyl ether, 10 mg of6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained, flash point 208° C.

EXAMPLE 206-[4-(2-Acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

9.4 mg of6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneand 0.04 ml of acetic acid anhydride in 0.5 ml of tetrahydrofuran arestirred for 2 days at room temperature, and mixed with ethyl acetate andsodium bicarbonate solution. The ethyl acetate solution is dried andconcentrated by evaporation. After chromatography on silica gel, 8 mg of6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained.

MS (ei): M⁽⁺⁾=510

EXAMPLE 215-[4-(2-Acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide

is obtained analogously to Example 20 from5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide,flash point 125° C.

EXAMPLE 225-[4-(5-Fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide

17.7 mg of5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide,0.4 ml of pyridine and 0.078 ml of mesyl chloride are stirred for 17hours at room temperature, mixed with ethyl acetate, and washed threetimes with 1N hydrochloric acid. The ethyl acetate solution is dried andconcentrated by evaporation. After chromatography on silica gel withethyl acetate/hexane (1:1), 11 mg of5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalideis obtained, flash point 218° C.

EXAMPLE 236-[4-(2-Bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

is obtained analogously to Example 3 from6-[4-(2-bromo-3-methoxyphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one,MS (esi): M⁽⁺⁾+1=543 (⁷⁹Br) and 545 (⁸¹Br)

Separation of the Enantiomers of Example 23:

The enantiomer mixture of Example 23 is separated by chromatography onchiral support medium (CHIRALPAK AD®, DAICEL Company) withhexane/ethanol (93:7, vv). Thus obtained from 200 mg of racemate are:

-   (−)-6-[4-(2-Bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one    as a first fraction: 86 mg, [flash point 233-235° C., α_(D)=−81.4°    (c=0.5 in chloroform)] and-   (+)-6-[4-(2-Bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one    as a second fraction: 82 mg.

EXAMPLE 24(+)-6-[4-(2-Bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

78 mg of(+)-6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-oneis mixed in 1.4 ml of dichloromethane at 0° C. with 0.71 ml of a 1 molarsolution of boron tribromide in dichloromethane. After 2 hours ofstirring at 0° C., the mixture is added to water, extracted with ethylacetate, the organic phase is dried (Na₂SO₄) and concentrated byevaporation. After the residue is triturated with hexane, the titlecompound is obtained in crystalline form, flash point 226-231° C.,[α]_(D)=+91.1° (c=0.5 in chloroform)

EXAMPLE 25(−)-6-[4-(2-Bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

Example 25 is produced analogously to Example 24 starting from thecorresponding(−)-6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one.Flash point 227-231° C., [α]_(D)=−94.3° (c 0.5 in chloroform).

EXAMPLE 266-[4-(2,3-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

Precursors:

2-Methyl-2-(2,3-difluorophenyl)butyronitrile and2-methyl-2-(2,6-difluorophenyl)butyronitrile

A solution of 5.0 g (37.85 mmol) of 1,2,3-trifluorobenzene, 3.30 g(39.74 mmol) of 2-methylbutylnitrile and 75.7 ml (0.5 M in toluene) ofpotassium-bis-trimethylsilylamide in 182 ml of toluene is heated for 3hours at 60° C. It is mixed with ice water and ether. The organic phaseis acidified with 10% H₂SO₄ and washed three times with water, dried(Na₂SO₄) and concentrated by evaporation in a vacuum. Afterchromatography on silica gel with 0-4% ether-hexane, 3.8 g of2-methyl-2-(2,3-difluorophenyl)butyronitrile and 1.6 g of2-methyl-2-(2,6-difluorophenyl)butyronitrile are obtained.

-   2-Methyl-2-(2,3-difluorophenyl)butyronitrile:

¹H-NMR (CDCl₃), δ (ppm)=0.88 (t, 3H), 1.81 (s, 3H), 1.95-2.1 (m, 1H),2.1-2.25 (m, 1H), 7.05-7.2 (m, 2H), 7.3-7.4 (m, 1H).

-   2-Methyl-2-(2,6-difluorophenyl)butyronitrile:

¹H-NMR (CDCl₃), δ (ppm)=1.06 (t, 3H), 1.89 (t, 3H), 1.95-2.1 (m, H),2.15-2.3 (m, H), 6.85-6.95 (m, 2H), 7.2-7.3 (m, 1H).

2-(2,3-Difluorophenyl)-2-methylbutyraldehyde

Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,2-(2,3-difluorophenyl)-2-methylbutyronitrile is obtained as a colorlessoil.

¹H-NMR (CDCl₃), δ (ppm)=0.79 (t, 3H), 1.41 (s, 3H), 1.85-2.0 (m, 1H),2.0-2.15 (m, 1H), 7.0-7.3 (m, 3H), 9.68 (d, 1H).

4-(2,3-Difluorophenyl)-4-methyl-2-oxocaproic acid

Analogously to the process that is described for4-(5-fluoro-2-methyphenyl)-4-methyl-2-oxovaleric acid,4-(2,3-difluorophenyl)-4-methyl-2-oxocaproic acid is obtained: ¹H-NMR(CDCl₃), δ (ppm) 0.71 (t, 3H), 1.47 (s, 3H), 1.7 (m, H), 2.0 (m, 1H),3.26 (d, 1H), 3.74 (d, 1H), 6.9-7.1 (m, 3H).

6-[4-(2,3-Difluorophenyl)-4-methyl-2-oxocaproylamino]-4-methyl-2,3-benzoxazin-1-one

Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-[4-(2,3-difluorophenyl)-4-methyl-2-oxocaproylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained:

¹H-NMR (CDCl₃), δ (ppm)=0.73 (t, 3H), 1.5 (s, 3H), 1.7 (m, 1H), 2.05 (m,1H), 2.58 (s, 3H), 3.37 (d, 1H), 3.84 (d, 1H), 7.0 (m, 3H), 7.72 (dd,1H), 8.24 (d, 1H), 8.33 (d, 1H), 9.0 (bs, 1H).

6-[4-(2,3-Difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained. The diastereomer mixture is separated by chromatography onsilica gel with 20-100% ethyl acetate/hexane.

Diastereomer 1: ¹H-NMR (CDCl₃), δ (ppm)=0.66 (t, 3H), 1.39 (s, 3H), 1.7(m, 1H), 2.1 (m, 1H), 2.61 (s, 3H), 2.7 (m, 2H), 6.9-7.2 (m, 3H), 7.67(dd, 1H), 8.31 (d, 1H), 8.37 (d, 1H), 8.8 (s, 1H)

Diastereomer 2: ¹H-NMR (CDCl₃), δ (ppm)=0.62 (t, 3H), 1.59 (s, 3H), 1.6(m, 1H), 2.15 (m, 1H), 2.23 (d, 1H), 2.55 (s, 3H), 3.07 (d, 1H), 6.58(m, 1H), 6.71 (m, 1H), 6.92 (m, 1H), 7.46 (dd, 1H), 8.01 (d, 1H), 8.27(d, 1H), 8.3 (s, 1H)

EXAMPLE 276-[4-(2,6-Difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

Precursors:

2-(2,6-Difluorophenyl)-2-methylbutyraldehyde

Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,2-(2,6-difluorophenyl)-2-methylbutyronitrile is obtained as a colorlessoil.

¹H-NMR (CDCl₃), δ (ppm)=0.83 (t, 3H), 1.49 (t, 3H), 1.9-2.1 (m, 2H),6.85-6.95 (m, 2H), 7.2-7.3 (m, 1H), 9.69 (t, 1H).

4-(2,6-Difluorophenyl)-4-methyl-2-oxocaproic acid

Analogously to the process that is described for4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid,4-(2,6-difluorophenyl)-4-methyl-2-oxocaproic acid is obtained: ¹H-NMR(CDCl₃), δ (ppm)=0.76 (t, 3H), 1.62 (t, 3H), 1.7 (m, H), 1.9 (m, 1H),3.0 (dt, 1H), 4.0 (d, 1H), 6.8 (m, 2H), 7.13 (m, 1H).

6-[4-(2,6-Difluorophenyl)-4-methyl-2-oxocaproylamino]-4-methyl-2,3-benzoxazin-1-one

Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-[4-(2,6-difluorophenyl)-4-methyl-2-oxocaproylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained:

¹H-NMR (CDCl₃), δ (ppm)=0.81 (t, 3H), 1.64 (t, 3H), 1.77 (m, 1H), 1.96(m, 1H), 2.5 (s, 3H), 3.12 (dt, 1H), 4.09 (d, 1H), 6.8 (m, 2H), 7.15 (m,1H), 7.77 (dd, 1H), 8.30 (d, 1H), 8.34 (d, 1H), 9.1 (bs, 1H).

6-[4-(2,6-Difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained as a diastereomer mixture: ¹H-NMR (CDCl₃), δ (ppm)=0.7 (m,3H), 1.4 (m, 1H), 1.5, 1.7, (2t, 3H), 2.0-3.2 (m, 6H), 6.4-7.3 (m, 3H),7.4-8.4 (m, 3H), 8.5, 8.9 (2bs, 1H).

EXAMPLE 286-{3-[4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one

Precursors:

4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-carbonitrile

6.76 g of (2-chloro-5-fluorophenyl)-acetonitrile and 5.7 ml of2,2-dichlorodiethyl ether are dissolved in 100 ml of dimethylformamideand mixed within 2.5 hours with 3.7 g of sodium hydride (60%) whilebeing cooled with ice. After 3 hours at 0° C. and 16 hours at roomtemperature, it is mixed with ice water and ethyl acetate, acidifiedwith 1 M hydrochloric acid, and the ethyl acetate phase is washed withwater, dried (Na₂SO₄) and concentrated by evaporation. Afterchromatography on silica gel, 6.2 g of4-(2-chloro-5-fluorophenyl)-4-pyranylcarbonitrile, flash point 91-93°C., is obtained.

4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-carbaldehyde

Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-carbaldehyde is obtainedas a colorless oil, boiling point 145° C./0.04 hPa.

3-[4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-oxopropionic acid

Analogously to the process that is described for4-(5-fluoro-2-methylphenyl)-4-methyl-oxavaleric acid,3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-oxo-propionicacid is obtained, flash point 158° C.

6-{3-[4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1-one

Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1-oneis synthesized.

Flash point 206-208° C.

6-{3-[4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one

Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one,6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-oneis synthesized. Flash point 224-226° C.

Separation of Enantiomers of Example 28:

The enantiomer mixture of Example 28 is separated by chromatography onchiral support medium (CHIRALPAK AD®, DAICEL Company) withhexane/ethanol (9:1, vv). Thus obtained from 300 mg of racemate are:

-   (−)-6-{3-[4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one    as a first fraction, 129 mg, flash point 181-183° C., [α_(D)=−83.2°    (c=0.5 in tetrahydrofuran)] and-   (+)-6-{3-[4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one    as a second fraction, 129 mg, flash point 181-183° C.

EXAMPLE 29

In the glucocorticoid receptor-(GR)-binding test with use of cytosolpreparations of Sf9 cells that have been infected with recombinantbaculoviruses, which code for the GR, and with use of 10 nM of[³H]-dexamethasone as a reference substance, (cf. Lefebvre et al. J.Steroid Biochem., 33, 557-563, 1989), the compounds of formula I show ahigh to very high affinity to the GR (see Table 9). TABLE 9 GR-BindingTest Compound IC₅₀ [mol/l] Example 38 <3.0 × 10⁻¹⁰ Example 16, compound26   1.6 × 10⁻⁸ Example 16, compound 33   1.1 × 10⁻⁹ Example 3, compound9 <3.0 × 10⁻¹⁰ Example 16, compound 16   6.2 × 10⁻¹⁰ Example 16,compound 13 <3.0 × 10⁻¹⁰ Dexamethasone   2.8 × 10⁻⁸ Prednisolone   4.0 ×10⁻⁸

EXAMPLE 30

The potency of the antiinflammatory action is determined in a cell testby the inhibition of the secretion of cytokine IL-8. The compounds ofgeneral formula I according to the invention inhibit the secretion ofcytokine IL-8 in the human monocyte cell line THP-1 that is triggered bylipopolysaccharide (LPS). The concentration of the cytokines wasdetermined in the supernatant by means of commercially available ELISAkits. In this connection, the compounds of formula I show a high to veryhigh potency and action in inhibition (see Table 10). TABLE 10 IL-8Values Inhibition of IL-8 Secretion IC50 Inhibition of IL-8 SecretionCompounds [mol/l] Effectiveness [%] Example 38 8.6 × 10−9 56 Example 16,4.3 × 10−9 77 compound 26 Example 16, 3.0 × 10−8 45 compound 33 Example3, 6.5 × 10−8 51 compound 9 Example 16, 1.0 × 10−8 80 compound 16Example 16, 9.6 × 10−9 58 compound 13 Prednisolone 2.4 × 10−8 95

EXAMPLE 31

The antiinflammatory actions of the compounds of general formula I weretested in the animal experiment in the croton oil-induced inflammationin rats and mice (J. Exp. Med. (1995), 182, 99-108). In this respect,croton oil in an ethanolic solution was administered topically to theears in the animals. The test substances were systemically administeredtwo hours before the croton oil. After 16-24 hours, the ear weight wasmeasured as a yardstick of the inflammatory edema. In this connection,the compounds of formula I show an inhibition of the croton-oil-inducedinflammation that is comparable to the standard (prednisolone) and issometimes also stronger (see Table 11). TABLE 11 Inhibition of EdemaFormation Edema inhibition Edema inhibition Compounds [%] with 3 mg/kg[%] with 30 mg/kg Example 38 58 101 Example 16, 11 81 compound 26Example 16, 77 86 compound 33 Example 3, 50 92 compound 9 Example 16, 5478 compound 16 Example 16, 47 106 compound 13 Prednisolone 35 84

EXAMPLE 32

As a parameter for the side effects of the steroid-induced catabolicmetabolism, the activity of the enzyme tyrosinamino transferase (TAT)was determined from liver homogenates by photometry. The activityrepresents a good yardstick of the undesirable metabolic actions of theglucocorticoids. To measure the TAT induction, the animals aresacrificed 8 hours after the test substances are administered, thelivers are removed, and the TAT activity in the homogenate is measured.In this test, at doses at which they have an antiinflammatory action,the compounds of general formula I induce little or no tyrosinaminotransferase in comparison to the steroids (Table 12). TABLE 12 Inductionof the Tyrosinamino Transferase Activity Induction factor* for TATInduction factor Compounds with 3 mg/kg for TAT with 30 mg/kg Example 381.2 6.0 Example 16, 1.4 3.7 compound 26 Example 16, 1.3 2.0 compound 16Prednisolone 2.6 8.0

-   -   The induction factor stands for the corresponding n-fold        increase in the tyrosinamino transferase enzyme activity in        treated animals compared to untreated animals.

1-8. (canceled)
 9. A compound of formula I

wherein R¹ and R² are the same or different and stand for a hydrogenatom, a C₁-C₅ alkyl group, or, together with the C-atom of the chain,stand for a ring with a total of 3-7 links; R³ is a straight-chain orbranched C₁-C₅ alkyl group or a straight-chain or branched, partially orcompletely fluorinated C₁-C₅ alkyl group; A stands for the group

wherein the dashed line means the interface site; R⁴ is methyl, nitro,amino, acetylamino, or mesylamino; R⁵, R⁶, and R⁸ are the same ordifferent from one another and are each a hydrogen atom, a halogen atom,a cyano group, a nitro group, a COOR⁹ group, a CONR¹⁰ group, or an NHR¹¹group, a straight-chain or branched C₁-C₅ alkyl group, a straight-chainor branched C₂-C₅ alkenyl group, a straight-chain or branched C₂-C₅alkinyl group, a straight-chain or branched C₁-C₅ alkyl group that ispartially or completely substituted by fluorine atoms, a C₁-C₅ acylgroup, an aryl radical or a heteroaryl radical; R⁷ is halogen; R⁹ is ahydrogen atom, a straight-chain or branched C₁-C₅ alkyl group or abenzyl group; R¹⁰ is a hydrogen atom or a straight-chain or branchedC₁-C₅ alkyl group; R¹¹ is a hydrogen atom, a straight-chain or branchedC₁-C₅ alkyl group, a straight-chain or branched, partially or completelyfluorinated C₁-C₅ alkyl group, a C₁-C₅ acyl group, an —SO₂—(C₁-C₅) alkylgroup or an —SO₂-phenyl group that is optionally substituted by halogenor a C₁-C₅ alkyl group; Ar is the ring system

X^(3a) and X^(3b) are the same or different and are each a hydrogenatom, a straight-chain or branched C₁-C₅ alkyl group, or astraight-chain or branched, partially or completely fluorinated C₁-C₅alkyl group; and X⁴, X⁶, and X⁷ are the same or different and are each ahydrogen atom, a straight-chain or branched C₁-C₅ alkyl group, astraight-chain or branched, partially or completely fluorinated C₁-C₅alkyl group, a halogen atom, a hydroxy group, a C₁-C₅ alkoxy group or aC₁-C₅ alkanoyloxy group; and physiologically compatible salts thereof,wherein said compound can also be in the form of a racemate or in theform of separate stereoisomers.
 10. A compound selected from thefollowing compounds:5-[4-(5-fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide;5-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide;5-[4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide;5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide;(−)5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide;(+)5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide;5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide;(−)5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide;(+)5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide;5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide;(−)5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide;(+)5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide;and physiologically compatible salts thereof.
 11. A compound accordingto claim 10, wherein said compound is selected from the followingcompounds:5-[4-(5-fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide;5-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide;5-[4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide;5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide;(−)5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide;(+)5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide;and physiologically acceptable salts thereof.
 12. A compound accordingto claim 10, wherein said compound is selected from the followingcompounds:5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide;(−)5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide;(+)5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide;and physiologically acceptable salts thereof.
 13. A compound accordingto claim 10, wherein said compound is selected from the followingcompounds:5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide;(−)5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide;(+)5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide;and physiologically acceptable salts thereof.
 14. A compound accordingto claim 10, wherein said compound is in the form of a hydrochloride,sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate,benzoate, mesylate, citrate or succinate salt.
 15. A pharmaceuticalcomposition comprising a compound according to claim 10 and apharmaceutically compatible vehicle.
 16. A pharmaceutical compositionaccording to claim 15, wherein said composition is in the form of atablet, coated tablet, capsule, pill, powder, granulate, lozenge,suspension, emulsion or solution.
 17. A pharmaceutical compositionaccording to claim 15, wherein said composition is in an injectable orinfusible form.
 18. A pharmaceutical composition according to claim 15,wherein said composition is in the form of an aqueous and oily injectionsolution or suspension.
 19. A pharmaceutical composition according toclaim 15, wherein said composition is in the form of a suppository,capsule, solution or ointment.
 20. A pharmaceutical compositionaccording to claim 15, wherein said composition is in the form of anaerosol or inhalant.
 21. A pharmaceutical composition according to claim15, wherein said composition is in the form of drops, ointment ortincture.
 22. A pharmaceutical composition according to claim 15,wherein said composition is in the form of a gel, ointment, fattyointment, cream, paste, powder, milk or tincture.
 23. A method forpreparing a pharmaceutical composition comprising formulating a compoundaccording to claim 10 with at least one vehicle, filler, substance thatinfluence decomposition, binding agent, humectant, lubricant, absorbent,diluent, flavoring corrective, or staining agent.
 24. A process forproduction of a compound according to claim 10, comprising: (a)optionally activating the acid function of an α-ketocarboxylic acid offormula II

wherein R¹ and R² are the same or different and are each a hydrogenatom, a C₁-C₅ alkyl group, or, together with the C-atom of the chain,stand for a ring with a total of 3-7 links, A is the group

 in which the dashed line means the interface site, R⁴ to R⁸ are thesame or different from one another and are each a hydrogen atom, ahalogen atom, a cyano group, a nitro group, a COOR⁹ group, a CONR¹⁰group, an NHR¹¹ group, a straight-chain or branched C₁-C₅ alkyl group, astraight-chain or branched C₂-C₅ alkenyl group, a straight-chain orbranched C₂-C₅ alkinyl group, a straight-chain or branched C₁-C₅ alkylgroup that is partially or completely substituted by fluorine atoms, aC₁-C₅ acyl group, an aryl radical or a heteroaryl radical, or R⁴ and R⁵together with the two carbon atoms of ring A mean a saturated orunsaturated carbocyclic ring with a total of 5-7 links, R⁹ stands for ahydrogen atom, a straight-chain or branched C₁-C₅ alkyl group or abenzyl group, R¹⁰ stands for a hydrogen atom or a straight-chain orbranched C₁-C₅ alkyl group, R¹¹ stands for a hydrogen atom, astraight-chain or branched C₁-C₅ alkyl group, a straight-chain orbranched, partially or completely fluorinated C₁-C₅ alkyl group, a C₁-C₅acyl group, an —SO₂—(C₁-C₅) alkyl group or an —SO₂-phenyl group that isoptionally substituted by halogen or a C₁-C₅ alkyl group; (b) reactingan α-ketocarboxylic acid of formula II, in which the acid function isoptionally activated, with a compound of formula VAr—NH—R¹³,  (V) wherein R¹³ is a hydrogen atom or a C₁-C₅ acyl group,and Ar is the ring system

in which X^(3a) and X^(3b) are the same or different and are each ahydrogen atom, a straight-chain or branched C₁-C₅ alkyl group, or astraight-chain or branched, partially or completely fluorinated C₁-C₅alkyl group, X⁴, X⁶, and X⁷ are the same or different and are each ahydrogen atom, a straight-chain or branched C₁-C₅ alkyl group, astraight-chain or branched, partially or completely fluorinated C₁-C₅alkyl group, a halogen atom, a hydroxy group, a C₁-C₅ alkoxy group or aC₁-C₅ alkanoyloxy group; (c) optionally cleaving off radical R¹³; and(d) reacting the resultant compound with a compound of formula III(R¹²)₃—SiR³  (III) in the presence of a catalyst and optionally cleavingoff radical R¹³, whereby a compound according to claim 9 is formed. 25.A process according to claim 24, wherein the acid function of thecompound of formula II is activated before reacting the compound offormula II with the compound of formula V.
 26. A process according toclaim 24, wherein the acid function of the compound of formula II isactivated by conversion into the acid chloride.
 27. A process accordingto claim 24, wherein the reaction with the compound of formula III isperformed before radical R¹³ is removed.
 28. A process according toclaim 25, wherein the reaction with the compound of formula III isperformed before radical R is removed.
 29. A process according to claim24, wherein R¹³ is H.
 30. A process according to claim 24, wherein R¹³is H.
 31. A process according to claim 24, wherein the reaction with acompound of formula III is performed in the presence of a catalystselected from fluoride salts and alkali carbonates.
 32. A process forproduction of a compound according to claim 10, comprising: (a)esterifying an α-ketocarboxylic acid of formula II

wherein R¹ and R² are the same or different and are each a hydrogenatom, a C₁-C₅ alkyl group, or, together with the C-atom of the chain,stand for a ring with a total of 3-7 links, A is the group

 in which the dashed line means the interface site, R⁴ to R⁸ are thesame or different from one another and are each a hydrogen atom, ahalogen atom, a cyano group, a nitro group, a COOR⁹ group, a CONR¹⁰group, an NHR¹¹ group, a straight-chain or branched C₁-C₅ alkyl group, astraight-chain or branched C₂-C₅ alkenyl group, a straight-chain orbranched C₂-C₅ alkinyl group, a straight-chain or branched C₁-C₅ alkylgroup that is partially or completely substituted by fluorine atoms, aC₁-C₅ acyl group, an aryl radical or a heteroaryl radical, or R⁴ and R⁵together with the two carbon atoms of ring A mean a saturated orunsaturated carbocyclic ring with a total of 5-7 links, R⁹ stands for ahydrogen atom, a straight-chain or branched C₁-C₅ alkyl group or abenzyl group, R¹⁰ stands for a hydrogen atom or a straight-chain orbranched C₁-C₅ alkyl group, R¹¹ stands for a hydrogen atom, astraight-chain or branched C₁-C₅ alkyl group, a straight-chain orbranched, partially or completely fluorinated C₁-C₅ alkyl group, a C₁-C₅acyl group, an —SO₂—(C₁-C₅) alkyl group or an —SO₂-phenyl group that isoptionally substituted by halogen or a C₁-C₅ alkyl group; (b) reactingthe esterified α-ketocarboxylic acid of formula II with a compound offormula III(R¹²)₃SiR³  (III) wherein R³ stands for a straight-chain or branchedC₁-C₅ alkyl group or a straight-chain or branched, partially orcompletely fluorinated C₁-C₅ alkyl group, and R¹² is a C₁-C₅-alkylgroup, in the presence of a catalyst, to form a compound of formula IV

in which the acid group is esterified; (d) cleaving the ester of anesterified compound of formula IV; (e) activating the acid function ofthe compound of formula IV; and (f) reacting the resultant compound witha compound of formula VAr—NH—R¹³,  (V) wherein R¹³ is a hydrogen atom or a C₁-C₅ acyl group,and Ar is the ring system

in which X^(3a) and X^(3b) are the same or different and are each ahydrogen atom, a straight-chain or branched C₁-C₅ alkyl group, or astraight-chain or branched, partially or completely fluorinated C₁-C₅alkyl group, X⁴, X⁶, and X⁷ are the same or different and are each ahydrogen atom, a straight-chain or branched C₁-C₅ alkyl group, astraight-chain or branched, partially or completely fluorinated C₁-C₅alkyl group, a halogen atom, a hydroxy group, a C₁-C₅ alkoxy group or aC₁-C₅ alkanoyloxy group, to form a compound according to claim
 9. 33. Aprocess according to claim 32, wherein the acid function of the compoundof formula IV is activated by conversion into the acid chloride.
 34. Aprocess according to claim 32, wherein the reaction with a compound offormula III is performed in the presence of a catalyst selected fromfluoride salts and alkali carbonates.
 35. A compound according to claim9, wherein R⁷ is fluoro.